平野 牧人 (ヒラノ マキト)

  • 医学科 臨床教授
Last Updated :2024/04/23

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    <報道関連出演・掲載一覧> ●2020/3/23  朝日放送「キャスト」  ALSについて ●2019/7/16  読売テレビ「情報ライブミヤネ屋」  ふるえの症状について ●2016/3/15  読売新聞  パーキンソン病について



  • 医学(大阪大学)


J-Global ID


  • パーキンソン病   小脳失調   遺伝子治療   Parkinson Disease   Ataxia   筋萎縮性側索硬化症   




  • ライフサイエンス / 神経科学一般


  • 2017年04月 - 現在  近畿大学脳神経内科准教授
  • 2010年04月 - 2017年03月  近畿大学医学部堺病院神経内科准教授
  • 2005年04月 - 2010年03月  奈良県立医科大学神経内科准教授
  • 2003年01月 - 2005年03月  奈良県立医科大学神経内科講師
  • 2002年  - 奈良県立医科大学助手


  •         - 1998年   大阪大学   医学研究科   医学
  •         - 1998年   大阪大学   Graduate School, Division of Medicine   Neuroscience
  •         - 1990年   大阪大学   医学部   医学科
  •         - 1990年   大阪大学   Faculty of Medicine


  • 日本神経学会   Societas Neurologica Japonica   



  • Makito Hirano; Motoi Kuwahara; Yuko Yamagishi; Makoto Samukawa; Kanako Fujii; Shoko Yamashita; Masahiro Ando; Nobuyuki Oka; Mamoru Nagano; Taro Matsui; Toshihide Takeuchi; Kazumasa Saigoh; Susumu Kusunoki; Hiroshi Takashima; Yoshitaka Nagai
    Scientific reports 13 1 17801 - 17801 2023年10月 
    Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.
  • Kazumasa Saigoh; Makito Hirano; Yoshiyuki Mitsui; Itsuki Oda; Atsuko Ikegawa; Makoto Samukawa; Keisuke Yoshikawa; Yuko Yamagishi; Susumu Kusunoki; Yoshitaka Nagai
    Journal of medical case reports 17 1 431 - 431 2023年10月 
    BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.
  • 抗NMDA受容体抗体及び抗MOG抗体陽性脳炎の一例
    久富 隆寛; 森田 顕; 定金 秀爾; 吉川 恵輔; 寒川 真; 桑原 基; 平野 牧人; 永井 義隆
    臨床神経学 63 6 407 - 407 (一社)日本神経学会 2023年06月
  • SURF1遺伝子に新規の複合ヘテロ接合体変異を認めたLeigh脳症の1例
    名村 仁志; 吉川 恵輔; 金 蓮姫; 寒川 真; 桑原 基; 平野 牧人; 永井 義隆
    臨床神経学 63 6 416 - 416 (一社)日本神経学会 2023年06月
  • 吉川 莉乃; 平野 牧人; 岡 伸幸; 寒川 真; 西郷 和真; 鈴木 秀和; 宇高 不可思; 橋口 昭大; 高嶋 博; 濱田 征宏; 中村 雄作; 永井 義隆; 楠 進
    末梢神経 33 2 358 - 358 日本末梢神経学会 2022年12月
  • 片麻痺性片頭痛の原因遺伝子CACNA1A遺伝子のバリアント評価
    小田 いつき; 團野 大介; 西郷 和真; 多田 陽香; 川下 理日人; 北村 重和; 平野 牧人; 寒川 真; 竹島 多賀夫; 永井 義隆
    日本頭痛学会誌 49 2 526 - 526 (一社)日本頭痛学会 2022年11月
  • SCA8関連筋萎縮性側索硬化症の表現型変異と治療戦略(Phenotypic variation and therapeutic strategy of SCA8-associated amyotrophic lateral sclerosis)
    Hirano Makito; Takehara Toshiyuki; Murayama Shigeo; Izumi Yuishin; Samukawa Makoto; Matsubara Tomoyasu; Saito Yuko; Saigoh Kazumasa; Nakamura Yusaku; Fukuda Kanji; Kusunoki Susumu; Nagai Yoshitaka
    臨床神経学 62 Suppl. S216 - S216 2022年10月
  • 平野 牧人; 竹原 俊幸; 村山 繁雄; 和泉 唯信; 寒川 真; 松原 知康; 斎藤 祐子; 西郷 和真; 中村 雄作; 楠 進; 永井 義隆
    神経治療学 39 6 S232 - S232 (一社)日本神経治療学会 2022年10月
  • 平野 牧人; 竹原 俊幸; 村山 繁雄; 和泉 唯信; 寒川 真; 松原 知康; 斎藤 祐子; 西郷 和真; 中村 雄作; 楠 進; 永井 義隆
    神経治療学 39 6 S232 - S232 (一社)日本神経治療学会 2022年10月
  • Ituki Oda; Daisuke Danno; Kazumasa Saigoh; Johanna Wolf; Norihito Kawashita; Makito Hirano; Makoto Samukawa; Shigekazu Kitamura; Shoji Kikui; Takao Takeshima; Yoshiyuki Mitsui; Susumu Kusunoki; Yoshitaka Nagai
    Neuroscience research 2022年03月 
    We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.
  • Kanako Fujii; Makito Hirano; Atsushi Terayama; Rino Inada; Yoshihiko Saito; Ichizo Nishino; Yoshitaka Nagai
    Neuromuscular Disorders 32 5 436 - 440 2022年01月
  • 片麻痺性片頭痛の原因遺伝子ATP1A2遺伝子のバリアント評価
    小田 いつき; 團野 大介; 西郷 和真; Johanna Wolf; 川下 理日人; 平野 牧人; 寒川 真; 竹島 多賀夫; 三井 良之; 永井 義隆
    日本頭痛学会誌 48 2 479 - 479 (一社)日本頭痛学会 2021年11月
  • Kristine Joyce Porto; Makito Hirano; Jun Mitsui; Ayaka Chikada; Takashi Matsukawa; Hiroyuki Ishiura; Tatsushi Toda; Susumu Kusunoki; Shoji Tsuji
    Journal of the neurological sciences 429 117623 - 117623 2021年10月 [査読有り]
    Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35-3.31, PI: 0.63-7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98-3.35; p = 2.56 × 10-12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88-2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.
  • 脊髄小脳失調症8型遺伝子異常を有する筋萎縮性側索硬化症患者の嚥下機能
    磯野 千春; 平野 牧人; 福田 寛二; 寒川 真; 西郷 和真; 中村 雄作; 楠 進
    臨床神経学 61 Suppl. S421 - S421 (一社)日本神経学会 2021年09月
  • Rino Inada; Makito Hirano; Nobuyuki Oka; Makoto Samukawa; Kazumasa Saigoh; Hidekazu Suzuki; Fukashi Udaka; Akihiro Hashiguchi; Hiroshi Takashima; Yukihiro Hamada; Yusaku Nakamura; Susumu Kusunoki
    Journal of neurology 268 8 2933 - 2942 2021年08月 [査読有り]
    BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.
  • パーキンソン病および関連疾患における非翻訳領域反復配列の解析
    平野 牧人; 寒川 真; 楠 進; 永井 義隆
    パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15回 94 - 94 Movement Disorder Society of Japan (MDSJ) 2021年07月
  • 竹内 啓喜; 柳本 諭志; 寒川 真; 山下 翔子; 平野 牧人; 楠 進; 菱澤 美樹; 岡 伸幸
    末梢神経 31 2 357 - 357 日本末梢神経学会 2020年12月
  • 片麻痺性片頭痛(HM)の原因遺伝子ATP1A2遺伝子の解析
    小田 いつき; 團野 大介; 西郷 和真; 菊井 祥二; 木村 卓; 平野 牧人; 寒川 真; 三井 良之; 竹島 多賀夫; 楠 進
    日本頭痛学会誌 47 2 O27 - 2 (一社)日本頭痛学会 2020年11月
  • 病理学的に確認されたATXN8OS関連筋萎縮性側索硬化症の最初の患者についての報告(The first patient with pathologically-definite ATXN8OS-associated amyotrophic lateral sclerosis)
    Hirano Makito; Murayama Shigeo; Izumi Yuishin; Samukawa Makoto; Matsubara Tomoyasu; Saigoh Kazumasa; Nakamura Yusaku; Kusunoki Susumu
    臨床神経学 60 Suppl. S345 - S345 2020年11月
  • 平野 牧人; 井上 貴美子; 伊藤 龍生; 寒川 真; 藤村 晴俊; 能勢 和宏; 楠 進; 中村 雄作
    神経治療学 37 6 S223 - S223 (一社)日本神経治療学会 2020年10月
  • Makito Hirano; Chiharu Isono; Makoto Samukawa; Kanji Fukuda; Susumu Kusunoki
    Parkinsonism & related disorders 78 98 - 99 2020年09月 [査読有り]
  • Makoto Samukawa; Naoko Nakamura; Makito Hirano; Miyuki Morikawa; Hanami Sakata; Ichizo Nishino; Rumiko Izumi; Naoki Suzuki; Hiroshi Kuroda; Kensuke Shiga; Kazumasa Saigoh; Masashi Aoki; Susumu Kusunoki
    European neurology 1 - 6 2020年06月 [査読有り]
    Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.
  • 井上 千鶴; 池川 敦子; 西郷 和真; 新井田 要; 平野 牧人; 木戸 滋子; 川下 理日人; 巽 純子; 田村 和朗; 三井 良之; 楠 進
    日本遺伝カウンセリング学会誌 41 2 124 - 124 (一社)日本遺伝カウンセリング学会 2020年06月
  • Makito Hirano; Wataru Satake; Nobuko Moriyama; Ken Saida; Nobuhiko Okamoto; Pei-Chieng Cha; Yutaka Suzuki; Susumu Kusunoki; Tatsushi Toda
    Journal of Human Genetics 2020年05月 [査読有り]
  • 桑原 基; 吉川 恵輔; 森川 みゆき; 稲田 莉乃; 寒川 真; 平野 牧人; 楠 進
    末梢神経 30 2 335 - 335 日本末梢神経学会 2019年12月
  • Effects of the rotigotine transdermal patch versus oral levodopa on swallowing in patients with Parkinson's disease.
    Hirano M; Isono C; Fukuda K; Ueno S; Nakamura Y; Kusunoki S
    J Neurol Sci 404 510  2019年09月 [査読有り]
  • Makito Hirano; Tatsuki Itoh; Harutoshi Fujimura; Kimiko Inoue; Makoto Samukawa; Kazuhiro Nose; Hikaru Sakamoto; Shunji Maekura; Shuichi Ueno; Takao Satou; Tsukasa Nishioka; Susumu Kusunoki; Yusaku Nakamura
    Journal of neuropathology and experimental neurology 2019年05月 [査読有り]
    Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis. The disease predominantly affects women (1:5-1:10), with only 3 reports of autopsy findings in women being published to date. The present study reports findings from the first autopsy performed on a man with anti-NMDAR encephalitis. The patient had some scattered lesions in the limbic system with neuronal loss, gliosis, and microglial activation. The temporal and frontal cortices showed additional patchy demyelination. T-lymphocyte infiltration was detectable in the fusiform gyrus lesion. These findings were partly similar to those reported in female patients. Although clinical differences based on the sex of the patient are reported for this disease, the observed pathological similarities potentially help to establish common therapeutic strategies for all patients. Severe testicular damage was additionally observed in the male patient in this study. Biopsy-proven severe testicular damage was also confirmed in another, previously fertile man who became azoospermic. Moreover, serum follicle-stimulating hormone levels, which often increased in response to disturbed spermatogenesis, were elevated, and testosterone/luteinizing hormone ratio reflecting Leydig cell function was low in all 5 male patients in this study. Overall, these findings suggest similar brain pathology in patients of both sexes and severe testicular damage in male patients.
  • PSP-Phenotype in SCA8: Case Report and Systemic Review.
    Samukawa M; Hirano M; Saigoh K; Kawai S; Hamada Y; Takahashi D; Nakamura Y; Kusunoki S
    Cerebellum 18 1 76 - 84 2019年02月 [査読有り]
  • Neurologic findings are the sole manifestations of a patient with cerebrotendinous xanthomatosis.
    Yamashita S; Hirano M; Yanagimoto S; Okazaki M; Sakai N; Kusunoki S
    Neurol Clin Neurosci 7 209 - 211 2019年 [査読有り]
  • Yoshikawa K; Kuwahara M; Saigoh K; Ishiura H; Yamagishi Y; Hamano Y; Samukawa M; Suzuki H; Hirano M; Mitsui Y; Tsuji S; Kusunoki S
    eNeurologicalSci 14 34 - 37 2019年 [査読有り]
    Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. Results: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.
  • Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene.
    Hirano M; Samukawa M; Isono C; Saigoh K; Nakamura Y; Kusunoki S
    Neurol Genet 4 4 e252  2018年08月 [査読有り]
  • Yuko Yamagishi; Kazumasa Saigoh; Yoshiro Saito; Ikuko Ogawa; Yoshiyuki Mitsui; Yukihiro Hamada; Makoto Samukawa; Hidekazu Suzuki; Motoi Kuwahara; Makito Hirano; Noriko Noguchi; Susumu Kusunoki
    Neuroscience research 128 58 - 62 2018年03月 [査読有り]
    Parkinson's disease (PD) is difficult to distinguish from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA); in addition, biomarker studies in PD mostly focused on those found in the cerebrospinal fluid, and there are few reports of simple biomarkers identified by blood analysis. Previously, the DJ-1 gene was identified as a causative gene of familial PD. Oxidized DJ-1 protein (oxDJ-1) levels were reported to increase in the blood of patients with unmedicated PD. Therefore, we determined the levels of oxDJ-1 in the erythrocytes of patients with PD, PSP, and MSA using ELISA. The oxDJ-1 levels were 165±117, 96±78, and 69±40ng/mg protein in the PD, PSP, and MSA groups, respectively. The mean level in disease control group was 66±31, revealing significant differences between the PD and PSP groups, the PD and MSA groups, and the PD and disease control groups. Our results indicated that oxDJ-1 levels in erythrocytes can be used as a marker for the differential diagnosis of PD.
  • Hiroyo Yoshino; Makito Hirano; A. Jon Stoessl; Yoko Imamichi; Aya Ikeda; Yuanzhe Li; Manabu Funayama; Ikuko Yamada; Yusaku Nakamura; Vesna Sossi; Matthew J. Farrer; Kenya Nishioka; Nobutaka Hattori
    NEUROBIOLOGY OF AGING 57 248.e7 - 248.e12 2017年09月 [査読有り]
    We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.A53V substitution albeit with an autosomal dominant pattern of disease inheritance (frequency 2/860 = 0.2%). The proband manifested slow and progressive parkinsonism at 55 years. Later she complicated with cognitive decline and hallucinations. Several of her immediate family members also presented with parkinsonism, cognitive decline, and psychosis. Positron emission tomography imaging of F-18-6-fluoro-L-dopa (F-18-DOPA) uptake, C-11(+) dihydrotetrabenzine (type 2 vesicular monoamine transporter), and 11C-d-threo-methylphenidate (a plasmalemmal dopamine transporter marker) binding in the striatum were significantly reduced. Hence, alpha-synuclein p.A53V homozygous mutation leads to a distinct phenotype of progressive parkinsonism and cognitive decline, commonly observed in patients with SNCA missense mutation or multiplications. (C) 2017 Elsevier Inc. All rights reserved.
  • Makito Hirano; Ryusuke Matsumura; Yusaku Nakamura; Kazumasa Saigoh; Hikaru Sakamoto; Shuichi Ueno; Hiroya Inoue; Susumu Kusunoki
    JOURNAL OF THE NEUROLOGICAL SCIENCES 378 75 - 79 2017年07月 [査読有り]
    Introduction: Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations Methods: Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed. Results: The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frame shift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable. Conclusions: Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease. (C) 2017 Elsevier B.V. All rights reserved.
  • Progression of dysphagia in spinocerebellar ataxia type 6.
    Isono C; Hirano M; Sakamoto H; Ueno S; Kusunoki S; Nakamura Y
    Dysphagia 32 420 - 426 2017年 [査読有り]
  • Makito Hirano; Yuko Yamagishi; Satoshi Yanagimoto; Kazumasa Saigoh; Yusaku Nakamura; Susumu Kusunoki
    EUROPEAN NEUROLOGY 78 1-2 78 - 83 2017年 [査読有り]
    To our knowledge, this is the first study to report the time course of radiological imaging of 3 patients from 2 families with VCP-related amyotrophic lateral sclerosis (ALS) and dementia. Both families shared the same p.Arg487His mutation in the VCP gene encoding valosin-containing protein. The first patient started to have a typical form of ALS, followed by dementia 7 years later. The second patient, a brother of the first one, had frontotemporal dementia and parkinsonism. The third patient had simultaneous ALS and dementia. All patients seemed to have progressive brain atrophy as their clinical symptoms progressed. The common and characteristic finding was atrophy of the temporal lobes including the hippocampi. The relation between imaging findings and symptoms varied considerably among the 3 patients. (C) 2017 S. Karger AG, Basel
  • 他の抗糖脂質抗体を伴ったGal-C抗体陽性GBSの臨床的・電気生理学的検討
    寒川 真; 上野 莉乃; 濱田 征宏; 桑原 基; 平野 牧人; 三井 良之; 楠 進
    臨床神経学 56 Suppl. S425 - S425 (一社)日本神経学会 2016年12月
  • Makito Hirano; Nobuyuki Oka; Akihiro Hashiguchi; Shuichi Ueno; Hikaru Sakamoto; Hiroshi Takashima; Yujiro Higuchi; Susumu Kusunoki; Yusaku Nakamura
    JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 21 4 370 - 374 2016年12月 [査読有り]
    Charcot-Marie-Tooth (CMT) disease is a complex of peripheral nervous system disorders. CMT type 2U (CMT2U) is an autosomal dominant (AD) disease caused by mutations in the MARS gene encoding methionyl-tRNA synthetase; this disease has thus been newly called AD-CMTax-MARS. A few families with mutations in the MARS gene have been reported, without detailed histopathological findings. We describe a 70-year-old woman who had bilateral dysesthesia of the soles since the age of 66 years. Sural nerve biopsy showed a decrease in the density of large myelinated nerve fibers. Increased clusters of regenerating myelinated nerve fibers were noted. Electronmicroscopic analyses revealed degeneration of unmyelinated nerves. There was no vasculitis or inflammatory cell infiltration. Genetic analysis identified a heterozygous p.P800T mutation, a reported mutation in the MARS gene. We report the detailed histopathological findings in a patient with CMT2U/AD-CMTax-MARS. The findings are similar to those found in CMT2D caused by mutations in the GARS gene, encoding glycyl-tRNA synthetase.
  • Saigoh K; Yoshimura S; Izumikawa T; Miyata S; Tabara Y; Matsushita T; Miki T; Miyamoto K; Hirano M; Kitagawa H; Kira JI; Kusunoki S
    Neuroscience research 108 55 - 59 2016年07月 [査読有り]
    Chondroitin sulfate proteoglycans (CSPGs) are a constituent of the matrix of the central nervous system (CNS), likely participating as regulatory molecules in the process of demyelination, remyelination, axonal degeneration and regeneration in the CNS. ChGn-1 is a key enzyme for production of CSPGs and knockout mice of this gene showed better recovery from spinal cord injury. We hypothesized that the clinical course of multiple sclerosis (MS) is influenced by the level of expression of ChGn-1 gene. We recruited 147 patients with MS and 181 healthy control subjects and analyzed single nucleotide polymorphisms (SNPs) of this gene. We found the coding SNP (cSNP: rs140161612) in approximately 10% of patients with MS as well as normal controls. The cSNP is changed from serine to leucine at position 126 (p.S126L). The expressed ChGn-1 mutant proteins exhibited no enzyme activities in COS-1 cells. In men, patients who had MS with S126L had a slower disease progression. This cSNP might be associated with the sex differences in clinical course of MS. (C) 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.
  • Samukawa M; Kuwahara M; Morikawa M; Ueno R; Hamada Y; Takada K; Hirano M; Mitsui Y; Sonoo M; Kusunoki S
    J Neuroimmunol. 301 61 - 64 2016年 [査読有り]
    Whether patients who have GBS with antibodies to galactocerebroside (Gal-C) and gangliosides (Gal-C-GS-GBS) more often have demyelinating or axonal neuropathy remains controversial. We assessed the electrophysiological data from 16 patients with Gal-C-GS-GBS based on the two established criteria to clarify this issue. In this largest cohort of Gal-C-GS-GBS, eight patients had demyelinating neuropathy and none exhibited axonal neuropathy on either criterion. These data indicated that antibodies to Gal-C, a myelin antigen, might predominantly be associated with demyelinating neuropathy, even in the presence of concomitant antibodies to gangliosides.
  • Makito Hirano; Yusaku Nakamura; Susumu Kusunoki
    Clinical Neurology 56 4 285 - 286 2016年 [査読有り]
  • Analyses of the VCP gene in Japanese patients with sporadic amyotrophic lateral sclerosis identify the novel mutation that increases susceptibility to oxidative stress.
    Makito Hirano; Yusaku Nakamura; Kazumasa Saigoh; Hikaru Sakamoto; Shuichi Ueno; Chiharu Isono; Susumu Kusunoki
    Ann Neurol 78 S 103 - 104 2015年10月 [査読有り]
  • Makito Hirano; Wataru Satake; Kenji Ihara; Ikuya Tsuge; Shuji Kondo; Ken Saida; Hiroyuki Betsui; Kazuhiro Okubo; Hikaru Sakamoto; Shuichi Ueno; Yasushi Ikuno; Ryu Ishihara; Hiromi Iwahashi; Mitsuru Ohishi; Toshiyuki Mano; Toshihide Yamashita; Yutaka Suzuki; Yusaku Nakamura; Susumu Kusunoki; Tatsushi Toda
    PLOS ONE 10 9 e0136317  2015年09月 [査読有り]
    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.
  • Makito Hirano; Chiharu Isono; Hikaru Sakamoto; Shuichi Ueno; Susumu Kusunoki; Yusaku Nakamura
    DYSPHAGIA 30 4 452 - 456 2015年08月 [査読有り]
    Abnormal swallowing, dysphagia, is a potentially fatal symptom in Parkinson's disease (PD) and is characterized by frequent silent aspiration, an unrecognized risk of suffocation and aspiration pneumonia. Several studies have reported that the injection of apomorphine, a dopamine agonist, alleviated dysphagia in some patients with PD. The effects of other antiparkinson medications against dysphagia remain controversial. Rotigotine is another dopamine agonist with non-oral administration, i.e., a transdermal patch. Its noninvasiveness seems to render this medicine even more suitable than apomorphine for dysphasic patients. However, no direct evidence has been reported. In the present retrospective open-label study, we for the first time objectively showed that rotigotine improved swallowing on videofluoroscopic examination in dysphagic patients with PD.
  • Makito Hirano; Yusaku Nakamura; Kazumasa Saigoh; Hikaru Sakamoto; Shuichi Ueno; Chiharu Isono; Yoshiyuki Mitsui; Susumu Kusunoki
    NEUROBIOLOGY OF AGING 36 3 1604.e1 - 6 2015年03月 [査読有り]
    Accumulating evidence has proven that mutations in the VCP gene encoding valosin-containing protein (VCP) cause inclusion body myopathy with Paget disease of the bone and frontotemporal dementia. This gene was later found to be causative for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, occurring typically in elderly persons. We thus sequenced the VCP gene in 75 Japanese patients with sporadic ALS negative for mutations in other genes causative for ALS and found a novel mutation, p.Arg487His, in 1 patient. The newly identified mutant as well as known mutants rendered neuronal cells susceptible to oxidative stress. The presence of the mutation in the Japanese population extends the geographic region for involvement of the VCP gene in sporadic ALS to East Asia. (C) 2015 Elsevier Inc. All rights reserved.
  • Kazumasa Saigoh; Jun Mitsui; Makito Hirano; Mitsuaki Shioyama; Makoto Samukawa; Yaeko Ichikawa; Jun Goto; Shoji Tsuji; Susumu Kusunoki
    PARKINSONISM & RELATED DISORDERS 21 3 332 - 334 2015年03月 [査読有り]
  • Yukihiro Hamada; Makito Hirano; Motoi Kuwahara; Makoto Samukawa; Kazuo Takada; Jyoji Morise; Keiko Yabuno; Shogo Oka; Susumu Kusunoki
    NEUROSCIENCE RESEARCH 91 63 - 68 2015年02月 [査読有り]
    Anti-myelin-associated-glycoprotein (MAG) neuropathy is an intractable autoimmune polyneuropathy. The antigenic region of MAG is the human natural killer-1 (HNK-1) carbohydrate. We and others previously suggested that the extension of antibody reactivities to HNK-1-bearing proteins other than MAG was associated with treatment resistance, without statistical analyses. In this study, we established an ELISA method with recombinant proteins to test binding specificities of currently available monoclonal antibodies to MAG and another HNK-1-bearing protein, phosphacan. Using this system, we found the distinct binding specificities of anti-MAG antibody in 19 patients with anti-MAG neuropathy. Their clinical relevance was then determined retrospectively with the adjusted 10-points INCAT disability score (0 = normal and 10 = highly disable). The results showed that strong reactivities of anti-MAG antibodies to phosphacan were significantly associated with treatment resistance or progressive clinical courses, indicating a possible clinical relevance of the binding specificities. (C) 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
  • Chiharu Isono; Makito Hirano; Hikaru Sakamoto; Shuichi Ueno; Susumu Kusunoki; Yusaku Nakamura
    EUROPEAN NEUROLOGY 74 5-6 237 - 242 2015年 [査読有り]
    Sporadic ataxia affecting multiple systems, such as cerebellar, extrapyramidal, and autonomic systems, is known as multiple system atrophy cerebellar type (MSA-C), while similar multisystem involvements are seen in certain types of hereditary ataxia, such as spinocerebellar ataxia type 3 (SCA3). Dysphagia is a common symptom that can predispose to aspiration pneumonia, a major cause of death in patients with these diseases. Although the progressions of dysphagia in patients with MSA-C have been reported sporadically, those in SCA3 have not been reported. We retrospectively compared the results of repetitive videofluoroscopic examinations in patients with SCA3 (n = 6) and in those with MSA-C (n = 7). The result showed that the gross progression of dysphagia was significantly slower in patients with SCA3 than in those with MSA-C, but the maximum progression speeds were not significantly different. The dysphagia severities were not associated with impaired activity of daily living evaluated by the Barthel index in MSA-C, but were associated in SCA3. Despite the small number of patients enrolled, these data suggest that physicians should monitor swallowing functions in patients with SCA3 after mild dysphagia develops because it may progress as rapidly as it does in MSA-C. (C) 2015 S. Karger AG, Basel
  • Ken Saida; Yuji Inaba; Makito Hirano; Wataru Satake; Tatsushi Toda; Yutaka Suzuki; Asuka Sudo; Shunsuke Noda; Yoshihiko Hidaka; Kazutaka Hirabayashi; Hiroki Imai; Toru Kurokawa; Kenichi Koike
    BRAIN & DEVELOPMENT 36 8 721 - 724 2014年09月 [査読有り]
    Bardet-Biedl syndrome (BBS) is a rare heterogeneous autosomal recessive disorder characterized by rod-cone dystrophy, postaxial polydactyly, truncal obesity, hypogonadism, learning disability, and renal anomaly that are caused by ciliary dysfunction. 16 genes have been associated with the BBS phenotype. Although recent pathophysiological studies using animal models have shown that ciliary dysfunction may induce hydrocephalus, there have been no reports of BBS with intracranial hypertension. We here describe a 9-year-old Japanese girl who was diagnosed as having BBS and later received renal transplantation due to chronic renal failure. She also exhibited intracranial hypertension, including papilledema and increased intrathecal pressure (260-300 mmH(2)O), but her brain magnetic resonance imaging was normal. No genetic abnormalities were detected by DNA chip analysis or exome sequencing. Her papilledema improved following administration of acetazolamide. This is the first report of a case of BBS complicated with intracranial hypertension and its treatment. (C) 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
  • Hikaru Sakamoto; Maiko Akamatsu; Makito Hirano; Kazumasa Saigoh; Shuichi Ueno; Chiharu Isono; Susumu Kusunoki; Yusaku Nakamura
    The superoxide dismutase-1 (SOD1) gene is the first gene for familial amyotrophic lateral sclerosis (ALS) with autosomal dominant inheritance. We describe a Japanese patient who had slowly progressive motor neuron disease with autonomic and sensory disturbances, urine incontinence and sensory neuropathy. This patient was found to have V31A mutation in the SOD1 gene. Although slow progression has been previously observed in patients with ALS caused by several mutations in the SOD1 gene, symptoms unrelated with motor systems are very rare. In addition, MRI showed cerebellar and brainstem atrophy, a finding previously unreported in SOD1-related ALS. The COQ2 gene, a gene very recently reported to be associated with multiple system atrophy, as well as genes for spinocerebellar ataxias was analyzed, the result of which showed no mutation in this patient. The V31A mutation is thus likely to be associated with atypical ALS affecting multiple systems.
  • Akitoshi Takeda; Hiroyuki Shimada; Akiko Tamura; Masaaki Yasui; Kei-ichi Yamamoto; Kazuhiro Itoh; Suzuka Ataka; Sayaka Tanaka; Masahiko Ohsawa; Hiroyuki Hatsuta; Makito Hirano; Hikaru Sakamoto; Shuichi Ueno; Yusaku Nakamura; Tsuyoshi Tsutada; Takami Miki
    MULTIPLE SCLEROSIS AND RELATED DISORDERS 3 3 391 - 397 2014年05月 [査読有り]
    Objective: To describe an unusual case of a male patient with anti-N-methyl-o-aspartate receptor (NMDAR) encephalitis who presented with multiple white matter lesions. Brain biopsy of the patient was performed, and follow-up evaluation of the cerebrospinal fluid (CSF) NMDAR antibody titer was implemented. Design: Case report. Setting: University hospital. Patient: A 35-year-old man with anti-NMDAR encephalitis initially presented with fever and psychiatric symptoms. After an initial attack of anti-NMDAR encephalitis, 2 atypical relapses occurred, which presented with myelitis and multifocal white matter lesions; the lesions were open-ring-shaped and partially enhanced. Intervention: Analysis of the brain biopsy specimen revealed the presence of demyelinated lesions with discrete borders. Subsequent intravenous methylprednisolone therapy resulted in improvement in the brain lesions. Prednisolone and cyclophosphamide were orally administered thereafter. Clinical progression of the disease paralleled observed changes in the CSF NMDAR antibody titer. Conclusion: The demyelinated lesions observed in this case were similar to lesions found in multiple sclerosis. On the basis of our finding that the clinical progression of the disease and the associated symptoms paralleled changes in the CSF NMDAR antibody titer, we speculate that the lesions formed as a result of anti-NMDAR encephalitis. (C) 2014 Elsevier By. All rights reserved.
  • Shuichi Ueno; Makito Hirano; Hikaru Sakamoto; Susumu Kusunoki; Yusaku Nakamura
    Case Reports in Neurology 6 2 222 - 225 2014年04月 [査読有り]
    We describe the first case of a patient with eyelid tremor probably associated with anti-contactin-associated protein-like 2 (Caspr2) antibody. Encephalitis associated with anti-voltage-gated potassium channel antibody is now attributed to autoantibodies against leucine-rich glioma inactivated 1 (Lgi1) and less frequently against Caspr2. Eyelid tremor or blepharoclonus is a rare or underdiagnosed involuntary movement that has been found in patients with infarction in the thalamus or drug-induced or idiopathic parkinsonism. Since patients with anti-Caspr2 antibody-related encephalitis occasionally have extrapyramidal signs, we speculate that the eyelid tremor was also caused by anti-Caspr2 antibody in our patient. Partial resolution of his symptoms by plasmapheresis also supported the involvement in immunological processes.
  • Titulaer MJ; Höftberger R; Iizuka T; Leypoldt F; McCracken L; Cellucci T; Benson LA; Shu H; Irioka T; Hirano M; Singh G; Cobo Calvo A; Kaida K; Morales PS; Wirtz PW; Yamamoto T; Reindl M; Rosenfeld MR; Graus F; Saiz A; Dalmau J
    Annals of neurology 75 3 411 - 428 2014年03月 [査読有り]
    Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p < 0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p = 0.011). Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis. Ann Neurol 2014;75:411-428
  • Samukawa M; Hamada Y; Kuwahara M; Takada K; Hirano M; Mitsui Y; Sonoo M; Kusunoki S; Japanese GBS; Study Group
    Journal of the neurological sciences 337 1-2 55 - 60 2014年02月 [査読有り]
    Introduction: Guillain-Barre syndrome (GBS) has often been associated with antibodies to glycolipids, such as galactocerebroside (Gal-C), a component of myelin. Whether patients who have GBS with anti-Gal-C antibody (Gal-C-GBS) more often have demyelinating neuropathy or axonal neuropathy remains controversial. Their clinical features have also been unestablished. Methods: We enrolled 47 patients with Gal-C-GBS. Their clinical and electrophysiological data were retrospectively reviewed and compared to 119 patients with CBS without anti-Gal-C antibody (non-Gal-C-GBS). Results: Demyelinating polyneuropathy occurred 4 times more frequently than axonal polyneuropathy in patients with Gal-C-GBS, but without statistical significance compared to patients with non-Gal-C-GBS (2.2:1). Patients with Gal-C-GBS had more frequent sensory deficits, autonomic involvements, and antecedent Mycoplasma pneumoniae (MP) infection than patients with non-Gal-C-GBS. Conclusions: This is the largest study clarifying the clinical and electrophysiological findings that more frequent sensory deficits, autonomic involvements, and antecedent MP infection are associated with Gal-C-GBS. (C) 2013 Elsevier B.V. All rights reserved.
  • Lidocaine静注療法が疼痛発作に有効であったFabry病の1例
    平野牧人; 東澤知輝; 熊井紫乃; 田中久夫; 阪本光; 上野周一; 小林正久; 楠 進; 中村雄作
    神経治療学 31 345 - 348 2014年 [査読有り]
  • Ikuko Ogawa; Kazumasa Saigoh; Makito Hirano; Yoshiyuki Mtsui; Koji Sugioka; Junko Takahashi; Yoshikazu Shimomura; Yoshihiko Tani; Yusaku Nakamura; Susumu Kusunoki
    Parkinsonism and Related Disorders 19 10 913 - 915 2013年10月 [査読有り]
  • Chiharu Isono; Makito Hirano; Hikaru Sakamoto; Shuichi Ueno; Susumu Kusunoki; Yusaku Nakamura
    DYSPHAGIA 28 3 413 - 418 2013年09月 [査読有り]
    Spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders frequently associated with autosomal dominant inheritance. SCA type 3 (SCA3) and SCA type 6 (SCA6) are the most common forms in Japan as well as the rest of the world. SCA3 affects multiple nervous systems while SCA6 affects mainly the cerebellar system. Dysphagia is clinically important since aspiration pneumonia is the most common cause of death in patients with SCA. We retrospectively studied dysphagia in 7 patients with SCA3 and 13 with SCA6 by videofluoroscopic examination of swallowing (VF). This is a larger series of patients with SCA6 than in previous studies, which had inconsistent results. Dysphagia was evaluated according to the scale established by the Japanese Society of Dysphagia Rehabilitation and the dysphagia outcome severity scale, an internationally used scale. The former separately evaluates oral and pharyngeal phases, while the latter concurrently grades both phases. Dysphagia according to the Japanese scale was mild but statistically significant in SCA6 and severe in SCA3. DOSS indicated abnormalities in SCA3 but not in SCA6. The swallowing abnormalities in SCA3 or SCA6 did not parallel the duration of disease or physical disability, suggesting that even patients with early disease or with well-preserved physical functions were at risk for aspiration. Our patients with dysphagia received percutaneous endoscopic gastrostomy-tube feeding at an appropriate time and underwent rehabilitation of swallowing. No patient had aspiration pneumonia. In conclusion, evaluation of swallowing ability by VF is essential for preventing aspiration in patients with SCA.
  • Masanori Ikeda; Makito Hirano; Keiich Shinoda; Noriyuki Katsumata; Daisuke Furutama; Katsuya Nakamura; Shu-Ichi Ikeda; Toshifumi Tanaka; Toshiaki Hanafusa; Hiroyuki Kitajima; Hitoshi Kohno; Mizuho Nakagawa; Yusaku Nakamura; Satoshi Ueno
    MUSCLE & NERVE 48 3 381 - 386 2013年09月 [査読有り]
    IntroductionTriple A syndrome is an autosomal recessive disease, characterized by esophageal achalasia, alacrima, and adrenal insufficiency, as well as involvement of the central, peripheral, and autonomic nervous systems. This disease mimics amyotrophic lateral sclerosis in some patients. The causative gene encodes ALADIN, a nuclear pore complex (NPC) component. Only 5 patients have been reported in Japan. MethodsWe conducted the first nationwide survey of triple A syndrome. Identified mutants were expressed as GFP-fusion proteins in cultured cells. ResultsTwo new patients were identified, and 1 had a novel mutation (p.Ser182fsX19). All mutant proteins tested were mislocalized from NPC to cytoplasm. ConclusionsThe most consistent neurological manifestation of triple A syndrome in Japanese patients was progressive bulbospinal muscular atrophy with both upper and lower motor neuron involvement, which mimicked motor neuron disease, similar to that seen in patients in Western countries. The identification of the new patients suggests that more cases are undiagnosed in Japan. Muscle Nerve48: 381-386, 2013
  • Hikaru Sakamoto; Makito Hirano; Kazuhiro Nose; Shuichi Ueno; Takashi Oki; Koichi Sugimoto; Tsukasa Nishioka; Susumu Kusunoki; Yusaku Nakamura
    Case Reports in Neurology 5 3 183 - 186 2013年09月 [査読有り]
    Background: Ganciclovir, a drug against cytomegalovirus (CMV) infection, is generally well tolerated, but can cause neurotoxicity such as encephalopathy. Although ganciclovir-induced encephalopathy has been described in several reports, a literature search revealed that ganciclovir concentrations in the blood or cerebrospinal fluid were previously measured in only 3 patients with encephalopathy. Symptoms usually include confusion and disturbed consciousness, which mimic CMV encephalitis. Prompt and accurate diagnosis is thus sometimes difficult, and is derived solely from accumulated clinical information of definite cases, since ganciclovir concentrations, not routinely measured, become available after several days or a few weeks. Case Presentation: Here, we summarize clinical information of all patients with definite ganciclovir-induced encephalopathy including our own patient, who had severe symptoms, with the highest reported trough concentration of ganciclovir in the blood, and underwent therapeutic dialysis with complete recovery. Conclusion: Our summary of patients with definite encephalopathy could lead to prompt and accurate diagnoses. © 2013 S. Karger AG, Basel.
  • Hikaru Sakamoto; Makito Hirano; Makoto Samukawa; Shuichi Ueno; Shunji Maekura; Harutoshi Fujimura; Motoi Kuwahara; Yukihiro Hamada; Chiharu Isono; Keiko Tanaka; Susumu Kusunoki; Yusaku Nakamura
    European Neurology 69 1 21 - 26 2013年02月 [査読有り]
    Anti-N-methyl-d-aspartate receptor (anti-NMDAR) antibody-associated encephalitis is an immunologic disease characterized by a female preponderance. Males are infrequently affected. The clinical symptoms of affected boys as well as girls have been summarized, and they have some clinical features distinct from those of adults. However, the characteristics of men have been described in only a few reports. We describe in detail four men with anti-NMDAR encephalitis who presented with several clinical features that complicated disease management and recovery, including venous thrombosis, bilateral hippocampal involvement, hypersexuality, and joint contracture. We also report the first detailed clinical information about a male patient who died of this disease. In addition, we summarize the clinical characteristics of five patients previously reported by others. © 2012 S. Karger AG, Basel.
  • 自己免疫疾患に関連する認知症
    平野牧人; 楠 進
    Modern Physician 33 34 - 37 2013年 [査読有り][招待有り]
  • Makito Hirano; Yusaku Nakamura; Kazumasa Saigoh; Hikaru Sakamoto; Shuichi Ueno; Chiharu Isono; Katsuichi Miyamoto; Maiko Akamatsu; Yoshiyuki Mitsui; Susumu Kusunoki
    NEUROLOGY 80 5 458 - 463 2013年01月 [査読有り]
    Objective: The purpose of this study was to find mutations in the SQSTM1 gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis (ALS), since this gene has been recently identified as a causative gene for familial and sporadic ALS in the United States. Methods: We sequenced this gene in 61 Japanese patients with sporadic and familial ALS. To our knowledge, we describe for the first time the clinical information of such mutation-positive patients. Results: We found novel mutations, p.Ala53Thr and p.Pro439Leu, in 2 patients with sporadic ALS. The clinical picture of the mutation-positive patients was that of typical ALS with varied upper motor neuron signs. Although this gene is causative for another disease, Paget disease of bone (PDB), none of our patients showed evidence of concomitant PDB. Conclusion: The presence of mutations in this racial population suggests worldwide, common involvement of the SQSTM1 gene in ALS. Neurology (R) 2013;80:458-463
  • Makoto Samukawa; Makito Hirano; Jun Tsugawa; Hikaru Sakamoto; Emi Tabata; Kazuo Takada; Motoi Kuwahara; Seiko Suzuki; Mari Kitada; Tatsuo Yamada; Hideo Hara; Yoshio Tsuboi; Yusaku Nakamura; Susumu Kusunoki
    NEUROSCIENCE RESEARCH 74 3-4 284 - 289 2012年12月 [査読有り]
    Acute disseminated encephalomyelitis causes multifocal demyelination in the central nerve system. Although this disease generally responds well to steroid therapy, it is occasionally steroid-resistant, leading to poor outcomes. Serological markers of prognosis are currently unavailable. We measured anti-glycolipid antibodies in 25 consecutive patients with acute disseminated encephalomyelitis, and found that four patients were positive for anti-galactocerebroside antibodies. All four patients had a poor response to steroids. We summarize clinical information on these four patients and three similar patients reported previously. This is the first report to describe concomitant involvement of the central nerve system and peripheral nervous system in anti-galactocerebroside antibody-associated acute disseminated encephalomyelitis, consistent with the location of galactocerebroside, and to document a dramatic response to repeated intravenous immunoglobulin therapy after unsuccessful steroid treatment in one patient. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
  • Makoto Samukawa; Makito Hirano; Hikaru Sakamoto; Mari Kitada; Susumu Kusunoki; Yusaku Nakamura
    MOVEMENT DISORDERS 26 14 2572 - 2573 2011年12月 [査読有り]
  • Takao Kiriyama; Makito Hirano; Takanori Kitauchi; Kozue Saito; Hiroshi Kataoka; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 113 8 693 - 695 2011年10月 [査読有り]
  • Makito Hirano; Yosuke Kokunai; Asami Nagai; Yusaku Nakamura; Kazumasa Saigoh; Susumu Kusunoki; Masanori P. Takahashi
    JOURNAL OF THE NEUROLOGICAL SCIENCES 309 1-2 9 - 11 2011年10月 [査読有り]
    Hypokalemic periodic paralysis (HypoPP) type 1 is an autosomal dominant disease caused by mutations in the Ca(V)1.1 calcium channel encoded by the CACNA1S gene. Only seven mutations have been found since the discovery of the causative gene in 1994. We describe a patient with HypoPP who had a high serum potassium concentration after recovery from a recent paralysis, which complicated the correct diagnosis. This patient and other affected family members had a novel mutation, p.Arg900Gly, in the CACNA1S gene. (C) 2011 Elsevier B.V. All rights reserved.
  • Kazuhiko Arima; Akira Kinoshita; Hiroyuki Mishima; Nobuo Kanazawa; Takeumi Kaneko; Tsunehiro Mizushima; Kunihiro Ichinose; Hideki Nakamura; Akira Tsujino; Atsushi Kawakami; Masahiro Matsunaka; Shimpei Kasagi; Seiji Kawano; Shunichi Kumagai; Koichiro Ohmura; Tsuneyo Mimori; Makito Hirano; Satoshi Ueno; Keiko Tanaka; Masami Tanaka; Itaru Toyoshima; Hirotoshi Sugino; Akio Yamakawa; Keiji Tanaka; Norio Niikawa; Fukumi Furukawa; Shigeo Murata; Katsumi Eguchi; Hiroaki Ida; Koh-ichiro Yoshiura
    Nakajo-Nishimura syndrome (NNS) is a disorder that segregates in an autosomal recessive fashion. Symptoms include periodic fever, skin rash, partial lipomuscular atrophy, and joint contracture. Here, we report a mutation in the human proteasome subunit beta type 8 gene (PSMB8) that encodes the immunoproteasome subunit beta 5i in patients with NNS. This G201V mutation disrupts the beta-sheet structure, protrudes from the loop that interfaces with the beta 4 subunit, and is in close proximity to the catalytic threonine residue. The beta 5i mutant is not efficiently incorporated during immunoproteasome biogenesis, resulting in reduced proteasome activity and accumulation of ubiquitinated and oxidized proteins within cells expressing immunoproteasomes. As a result, the level of interleukin (IL)-6 and IFN-gamma inducible protein (IP)-10 in patient sera is markedly increased. Nuclear phosphorylated p38 and the secretion of IL-6 are increased in patient cells both in vitro and in vivo, which may account for the inflammatory response and periodic fever observed in these patients. These results show that a mutation within a proteasome subunit is the direct cause of a human disease and suggest that decreased proteasome activity can cause inflammation.
  • Han-Xiang Deng; Wenjie Chen; Seong-Tshool Hong; Kym M. Boycott; George H. Gorrie; Nailah Siddique; Yi Yang; Faisal Fecto; Yong Shi; Hong Zhai; Hujun Jiang; Makito Hirano; Evadnie Rampersaud; Gerard H. Jansen; Sandra Donkervoort; Eileen H. Bigio; Benjamin R. Brooks; Kaouther Ajroud; Robert L. Sufit; Jonathan L. Haines; Enrico Mugnaini; Margaret A. Pericak-Vance; Teepu Siddique
    NATURE 477 7363 211 - U113 2011年09月 [査読有り]
    Amyotrophic lateral sclerosis (ALS) is a paralytic and usually fatal disorder caused by motor-neuron degeneration in the brain and spinal cord. Most cases of ALS are sporadic but about 5-10% are familial. Mutations in superoxide dismutase 1 (SOD1)(1,2), TAR DNA-binding protein (TARDBP, also known as TDP43)(3,4) and fused in sarcoma (FUS, also known as translocated in liposarcoma (TLS))(5,6) account for approximately 30% of classic familial ALS. Mutations in several other genes have also been reported as rare causes of ALS or ALS-like syndromes(7-15). The causes of the remaining cases of familial ALS and of the vast majority of sporadic ALS are unknown. Despite extensive studies of previously identified ALS-causing genes, the pathogenic mechanism underlying motor-neuron degeneration in ALS remains largely obscure. Dementia, usually of the frontotemporal lobar type, may occur in some ALS cases. It is unclear whether ALS and dementia share common aetiology and pathogenesis in ALS/dementia. Here we show that mutations in UBQLN2, which encodes the ubiquitin-like protein ubiquilin 2, cause dominantly inherited, chromosome-X-linked ALS and ALS/dementia. We describe novel ubiquilin 2 pathology in the spinal cords of ALS cases and in the brains of ALS/dementia cases with or without UBQLN2 mutations. Ubiquilin 2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins. Functional analysis showed that mutations in UBQLN2 lead to an impairment of protein degradation. Therefore, our findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention.
  • Kazuma Sugie; Masami Morikawa; Toshiaki Taoka; Makito Hirano; Satoshi Ueno
    JOURNAL OF NEUROIMAGING 21 1 79 - 82 2011年01月 [査読有り]
    Tolosa-Hunt syndrome (THS) is a very rare, relapsing, and remitting painful ophthalmoplegia caused by nonspecific granulomatous inflammation in the cavernous sinus. To our knowledge, bilateral complete, simultaneous palsies of all 3 cranial nerves associated with extraocular movement have not been reported. We describe the first such patient with bilateral THS that responded quickly to corticosteroid therapy. A 54-year-old man presented with a periorbital and frontal headache with acute bilateral severe blepharoptosis and fixed eyes, which dramatically responded to corticosteroid therapy. He had diabetes mellitus type II. Brain MRI showed granulomatous inflammation in both cavernous sinuses and thickening of the surrounding dura mater of the cranial base, suggesting the coexistence of focal hypertrophic cranial pachymeningitis. Our experience indicates that steroid therapy with strict control of blood sugar should be considered in patients with THS complicated by diabetes. MRI is a valuable tool for serially monitoring the response of lesions to treatment in THS.
  • Makito Hirano; Mitsuru Ohishi; Toshihide Yamashita; Yasushi Ikuno; Hiromi Iwahashi; Toshiyuki Mano; Ryu Ishihara; Ichiro Tanaka; Keiko Yanagihara; Chiharu Isono; Hikaru Sakamoto; Yusaku Nakamura; Susumu Kusunoki
    Clinical Medicine Insights: Case Reports 4 17 - 20 2011年 [査読有り]
    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod- cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-14. In the Western countries, the prevalence of this disease ranges from 1/13,500 to 1/160,000, while only a few Japanese patients have been reported in the English-language literature. The incidence of renal dysfunction or anomalies in previous reports varies considerably ranging from ~20% to universal occurrence. We here report that two Japanese patients who had BBS with normal BUN and creatinine levels had elevated levels of cystatin C, a sensitive marker of glomerular filtration rate. A urine albumin level increased only in the elder patient. Thus, cystatin C may be useful for detecting renal abnormalities in patients with an apparent normal renal function. Because this disease is diagnosed by accumulation of symptoms, such a sensitive marker might help early diagnosis of BBS. © the author(s), publisher and licensee Libertas Academica Ltd.
  • 常染色体劣性遺伝パーキンソニズムのparkin機能欠損に対するアンチセンス治療の検討
    浅井 宏英; 平野 牧人; 桐山 敬生; 池田 真徳; 上野 聡
    臨床神経学 50 12 1078 - 1078 (一社)日本神経学会 2010年12月
  • Kozue Saito; Makito Hirano; Toshiaki Taoka; Hiroyuki Nakagawa; Takanori Kitauchi; Emi Tanizawa; Koichi Yoshida; Yoshihiko Sakurai; Kentaro Tamura; Hiroyuki Nakase; Akira Yoshioka; Toshisuke Sakaki; Kimihiko Kichikawa; Satoshi Ueno
    JOURNAL OF NEUROIMAGING 20 3 284 - 286 2010年07月 [査読有り]
    Rotational vertebral artery (VA) occlusion can cause ischemic strokes due to hemodynamic insufficiency and possibly artery-to-artery (A-to-A) embolism. The former is known as bow hunter's stroke. The latter has been proposed only from indirect evidence. We have described a 7-year-old boy with cerebral infarction associated with A-to-A embolism due to repetitive rotational VA occlusion. He had a mobile mural thrombus at the VA occlusion site on head rotation. Surgical treatment may effectively prevent recurrences.
  • Hirohide Asai; Makito Hirano; Takao Kiriyama; Masanori Ikeda; Satoshi Ueno
    Intranuclear events due to mutations in the Parkin gene remain elusive in autosomal recessive juvenile parkinsonism (ARJP) We identified a mutant PARKIN protein in fibroblast cultures from a pair of siblings with ARJP who were homozygous for the exon 4-deleted Parkin gene Disease was mild in one patient and debilitating in the other. The detected mutant, encoded by a transcript lacking exon 3 as well as exon 4, is an in-frame deletion that removes 121 aa, resulting in a 344-aa protein (PaDel3A). Cell culture and transfection studies revealed negative correlations between expression levels of PaDel3,4 and those of cell cycle proteins, including cyclin E, CDK2, ppRb, and E2F-1, and demonstrated that GFP-PaDel3,4 entered nucleus and ubiquitinated cyclin E as a part of SCF(hSel-10) ligase complex in the patient cells. In addition, nuclear localization signal-tagged PaDel3,4 expressed in the transfected patient cells most effectively ubiquitinated cyclin E and reduced DNA damage, protecting cells from oxidative stress. Antisense-oligonucleotide treatment promoted skipping of exon 3 and thus generated PaDel3,4, increasing cell survival Collectively, we propose that naturally- and experimentally-induced exon skipping at least partly restores the mutant Parkin gene deficit, providing a molecular basis for the development of therapeutic exon skipping (C) 2009 Elsevier Inc All rights reserved,
  • Saito K; Hirano M; Taoka T; Nakagawa H; Kitauchi T; Ikeda M; Tanizawa E; Kichikawa K; Ueno S
    Clinical medicine insights. Case reports 3 1 - 4 2010年 [査読有り]
  • 遺伝性脊髄小脳変性症14型関連変異protein kinase Cγによる酸化ストレス下での細胞死
    浅井 宏英; 平野 牧人; 桐山 敬生; 池田 真徳; 降矢 芳子; 上野 聡
    臨床神経学 49 12 982 - 982 (一社)日本神経学会 2009年12月
  • DNA修復蛋白XRCC1の核局在シグナルを用いたAprataxinとSOD1の核内輸送
    桐山 敬生; 平野 牧人; 浅井 宏英; 池田 真徳; 降矢 芳子; 上野 聡
    臨床神経学 49 12 1021 - 1021 (一社)日本神経学会 2009年12月
  • 遺伝性脊髄小脳変性症14型の原因となる変異protein kinase Cγ活性と蛋白凝集の関連
    平野 牧人; 浅井 宏英; 桐山 敬生; 池田 真徳; 降矢 芳子; 上野 聡
    臨床神経学 49 12 1117 - 1117 (一社)日本神経学会 2009年12月
  • 平野 牧人; 森 俊雄; 池田 真徳; 浅井 宏英; 桐山 敬生; 降矢 芳子; 上野 聡
    日本放射線影響学会大会講演要旨集 52回 69 - 69 (一社)日本放射線影響学会 2009年11月
  • Hirohide Asai; Makito Hirano; Keiji Shimada; Takao Kiriyama; Yoshiko Furiya; Masanori Ikeda; Takaaki Iwamoto; Toshio Mori; Kazuto Nishinaka; Noboru Konishi; Fukashi Udaka; Satoshi Ueno
    HUMAN MOLECULAR GENETICS 18 19 3533 - 3543 2009年10月 [査読有り]
    Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease caused by mutations in the gene encoding protein kinase C gamma (PKC gamma). We report an SCA14 family with a novel deletion of a termination-codon-containing region, resulting in a missense change and a C-terminal 13-amino-acid extension with increased kinase activity. Notably, one patient with a severe phenotype is the first homozygote for the mutation causing SCA14. We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (APTX), a DNA repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant PKC gamma, and phosphorylation inhibited its nuclear entry. The phosphorylated residue was Thr111, located adjacent to the nuclear localization signal, and disturbed interactions with importin alpha, a nuclear import adaptor. Decreased nuclear APTX increased oxidative stress-induced DNA damage and cell death. Phosphorylation-resistant APTX, kinase inhibitors, and antioxidants may be therapeutic options for SCA14.
  • Hirohide Asai; Makito Hirano; Yoshiko Furiya; Fukashi Udaka; Masami Morikawa; Takashi Kanbayashi; Tetsuo Shimizu; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 111 4 341 - 344 2009年05月 [査読有り]
    Objectives: Sleep attacks (SAs) in Parkinson's disease (PD) are rare, but clinically important because they significantly impair the daily lives of patients. Causes of SAs include long-term activation of dopaminergic (especially D3) receptors. Recent studies suggest that SAs in PD may be related to impairment of hypothalamic orexin neurons, similar to narcolepsy. Whether orexin is associated with long-term activation of dopaminergic receptors remains uncertain. Patients and methods: We measured levels of orexin in samples of spinal cerebrospinal fluid (CSF) from 25 patients with PD, including 9 with excessive daytime sleepiness and 4 with SAs. Furthermore, in the four patients with SAs, the selective dopamine D1/D2 agonist pergolide was substituted for the causative drugs with D3 stimulatory activity, and CSF-orexin levels were measured before and after switching treatment. Results: In the 25 patients with PD, including the 4 patients with SAs, lower CSF-orexin levels were associated with a longer disease duration, which has been linked to a higher incidence of SAs. Switching treatment to pergolide significantly increased CSF-orexin levels and completely resolved SAs in the four patients with PD. Conclusion: Despite the small number of patients studied, our results suggest that orexin transmission is most likely involved in SAs in PD and that abrogation of D3 receptor stimulation may increase orexin and thereby inhibit SAs. (C) 2008 Elsevier B.V. All rights reserved.
  • H. Kataoka; Maya Yanase; Makoto Kawahara; Hidehiro Hirabayashi; Toshiaki Yamanaka; Makito Hirano; Satoshi Ueno
    BMJ Case Reports 2009 2009年02月 [査読有り]
    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor disability of patients with Parkinson's disease (PD). Mental changes and other adverse events are common, but typically transient. Severe complications such as intracerebral haemorrhage or infection are rare, but 6 of 73 patients who underwent STN-DBS died of pneumonia, cardiac failure or pulmonary embolism. We describe a patient with PD who had sudden respiratory difficulty due to a fixed epiglottis after STN-DBS. This symptom was confirmed to be related to STN stimulation on fibre-optic examination of the larynx.
  • Yasuyo Tonomura; Makito Hirano; Keiji Shimada; Hirohide Asai; Masanori Ikeda; Hiroshi Kataoka; Ichiro Tanaka; Noboru Konishi; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 111 1 102 - 104 2009年01月 [査読有り]
    Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by rod-cone dystrophy, polydactyly, central obesity, mental retardation, and hypogonadism. Although many organs are involved in BBS, hyperammonemia caused by portal hypertension has been reported previously in only a single patient. We describe the second such patient with BBS and hyperammonemia, associated with fluctuating mental impairment. The patient was a 17-year-old boy with BBS. Esophageal, gastric. and rectal varices and mild hepatic dysfunction started to develop at 5 years of age. A liver biopsy showed dilated portal veins with mild fibrosis in portal tract. From the age of 17 years, he often had forced laughter with apparently normal consciousness. Laboratory examinations revealed hyperammonemia (112.2 mg/ml). Oral medication lowered the blood ammonia level to 69.9 mg/ml, reduced the frequency of forced laughter, and improved his IQ. Patients with BBS may have additional diseases or conditions that affect mental status, such as hyperammonemia. Physicians should explore the underlying causes of these conditions and treat such patients, who already have a compromised quality of life. (c) 2008 Elsevier B.V. All rights reserved.
  • Yoshiko Furiya; Makito Hirano; Masami Nomura; Hidehiro Asai; Takao Kiriyama; Satoshi Ueno
    BMJ case reports 2009 2009年 [査読有り]
    Autosomal dominant cerebellar ataxia (ADCA) includes heterogeneous neurodegenerative diseases with or without various neurological signs and symptoms. Ishikawa et al reported a new type of ADCA, named chromosome16q22.1 linked ADCA (16q-ADCA), attributed to a heterozygous C→T substitution in the 5' non-coding region of puratrophin-1 gene. We searched for this mutation in168 patients from 129 families with ADCA and found it in six patients. The patients generally showed late onset pure cerebellar ataxia similar to previous reports but two had mild axonal neuropathy and orthostatic hypotension (OH). Our results suggest that 16q-ADCA shows a broader clinical presentation than previously thought.
  • Kinoshita S; Sugie K; Kataoka H; Sugie M; Hirano M; Ueno S
    Clinical medicine. Case reports 2 17 - 20 2009年 [査読有り]
  • Kiriyama T; Hirano M; Kusunoki S; Morita D; Hirakawa M; Tonomura Y; Kitauchi T; Ueno S
    Clinical medicine. Case reports 2 51 - 4 2009年 [査読有り]
    Guillain-Barrè syndrome (GBS) is usually associated with symmetrical weakness, and therefore asymmetrical weakness may confuse diagnosis. We report on a patient with GBS subsequent to Campylobacter jejuni enteritis who had asymmetrical weakness with CNS involvement. The patient tested positive for anti-ganglioside antibodies, including anti-GM1 IgM, anti-GD1b IgG, and anti-GT1a IgG. Patients with GBS can manifest asymmetrical signs and symptoms attributable to CNS involvement. Prompt, accurate diagnosis and treatment of post-C. jejuni GBS is especially important because its prognosis is relatively poor.
  • Kozue Saito; Makito Hirano; Miyuki Kajitani; Toshiaki Taoka; Kimihiko Kichikawa; Satoshi Ueno
    INTERNAL MEDICINE 48 1 71 - 74 2009年 [査読有り]
    We report a patient who had cerebral infarction associated with heparin-induced thrombocytopenia ( HIT) during treatment of aseptic encephalitis. In patients with intracranial inflammation, such as ours, the possibility of HIT has to be considered when heparin is used, since inflammatory cerebral lesions often cause vascular damage, which is an aggravating factor for HIT-associated thrombosis.
  • Triple A症候群における核内輸送を可能にする核局在シグナルの同定
    桐山 敬生; 平野 牧人; 浅井 宏英; 降矢 芳子; 上野 聡
    臨床神経学 48 12 1148 - 1148 (一社)日本神経学会 2008年12月
  • 眼球運動失行と低アルブミン血症を伴う早発型脊髄小脳失調症におけるDNA損傷の蓄積
    平野 牧人; 浅井 宏英; 青木 正志; 島田 啓司; 降矢 芳子; 桐山 敬生; 小西 登; 糸山 泰人; 上野 聡
    臨床神経学 48 12 1155 - 1155 (一社)日本神経学会 2008年12月
  • Tomohisa Nishiwaki; Nobuhiko Kobayashi; Takaaki Iwamoto; Aya Yamamoto; Shigeki Sugiura; Yin-Chang Liu; Alain Sarasin; Yumiko Okahashi; Makito Hirano; Satoshi Ueno; Toshio Mori
    DNA REPAIR 7 12 1990 - 1998 2008年12月 [査読有り]
    To get a clue to understand how mutations in the XPD gene result in different skin cancer susceptibilities in patients with xeroderma pigmentosum (XP) or trichothiodystrophy (TTD), a thorough understanding of their nucleotide excision repair (NER) defects is essential. Here, we extensively characterize the possible causes of NER defects in XP-D and in TTD fibroblasts. The 3 XP-D cell strains examined were similarly deficient in repairing UV-induced cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs) from genomic DNA. The severity of NER defects correlated with their UV sensitivities. Possible alterations of TFIIH (which consists of 10 subunits including XPD) were then examined. All XP-D cell strains were normal in their concentrations of TFIIH, and displayed normal abilities to recruit TFIIH to sites of UV-induced DNA damage. However, replication protein A (RPA; single-stranded DNA binding protein) accumulation at DNA damage sites, which probably reflects the in vivo XPD helicase activity of TFIIH, is similarly impaired in all XP-D cell strains. Meanwhile, all 3 TTD cell strains had similar to 50% decreases in cellular TFIIH content. Importantly, 2 of the 3 TTD cell strains, which carry the major XPD mutations found in TTD patients, showed defective recruitment of TFIIH to DNA damage sites. Moreover, RPA accumulation at damage sites was impaired in all TTD cell strains to different degrees, which correlated with the severity of their NER defects. These results demonstrate that XP-D and TTD cells are both deficient in the repair of CPDs and 6-4PPs, but TTD cells have more multiple causes for their NER defects than do XP-D cells. Since TFIIH is a repair/transcription factor, TTD-specific alterations of TFIIH possibly result in transcriptional defects, which might be implication for the lack of increased incidence of skin cancers in TTD patients. (C) 2008 Elsevier B.V All rights reserved.
  • Furiya Y; Hirano M; Kusunoki S; Ueda M; Sugie K; Nishiwaki T; Ueno S
    Muscle & nerve 38 6 1630 - 1633 2008年12月 [査読有り]
    In this report we describe a 72-year-old woman who had cytomegalovirus infection-related Guillain-Barre syndrome (GBS) associated with multiple immunoglobulin M (IgM) anti-ganglioside antibodies. She became tetraplegic with respiratory failure, but recovered completely after intravenous immunoglobulin therapy and plasmapheresis. The serum contained high-titer IgM antibody activities to several gangliosides with disialosyl residues (GD1b, GD3, GT1b, GQ1b, and GT1a) and GD1a. These antibodies are often found in sera from patients with chronic sensory ataxic neuropathy, but they occur rarely in GBS.
  • 平野 牧人; 浅井 宏英; 桐山 敬生; 池田 真徳; 降矢 芳子; 森 俊雄; 安井 明; 上野 聡
    日本放射線影響学会大会講演要旨集 51回 88 - 88 (一社)日本放射線影響学会 2008年11月
  • Takao Kiriyama; Makito Hirano; Hirohide Asai; Masanori Ikeda; Yoshiko Furiya; Satoshi Ueno
    Triple A syndrome is an autosomal recessive neurological disease, mimicking motor neuron disease, and is caused by mutant ALADIN, a nuclear-pore complex component. We recently discovered that the pathogenesis involved impaired nuclear import of DNA repair proteins, including DNA ligase I and the cerebellar ataxia causative protein aprataxin. Such impairment was overcome by fusing classical nuclear localization signal (NLS) and 137-aa downstream sequence of XRCC1, designated stretched NLS (stNLS). We report here that the minimum essential sequence of stNLS (mstNLS) is residues 239-276, downsized by more than 100 aa. mstNLS enabled efficient nuclear import of DNA repair proteins in patient fibroblasts, functioned under oxidative stress, and reduced oxidative-stress-induced cell death, more effectively than stNLS. The stress-tolerability of mstNLS was also exerted in control fibroblasts and neuroblastoma cells. These findings may help develop treatments for currently intractable triple A syndrome and other oxidative-stress-related neurological diseases, and contribute to nuclear compartmentalization study. (c) 2008 Elsevier Inc. All rights reserved.
  • Deng Han-Xiang; Jiang Hujun; Fu Ronggen; Zhai Hong; Shi Yong; Liu Erdong; Hirano Makito; C. Dal Canto Mauro; Siddique Teepu
    HUMAN MOLECULAR GENETICS 17 15 2310 - 2319 2008年08月 [査読有り]
    Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with amyotrophic lateral sclerosis (ALS). Among more than 100 ALS-associated SOD1 mutations, premature termination codon (PTC) mutations exclusively occur in exon 5, the last exon of SOD1. The molecular basis of ALS-associated toxicity of the mutant SOD1 is not fully understood. Here, we show that nonsense-mediated mRNA decay (NMD) underlies clearance of mutant mRNA with a PTC in the non-terminal exons. To further define the crucial ALS-associated SOD1 fragments, we designed and tested an exon-fusion approach using an artificial transgene SOD1(T116X) that harbors a PTC in exon 4. We found that the SOD1(T116X) transgene with a fused exon could escape NMD in cellular models. We generated a transgenic mouse model that overexpresses SOD1(T116X). This mouse model developed ALS-like phenotype and pathology. Thus, our data have demonstrated that a 'mini-SOD1' of only 115 amino acids is sufficient to cause ALS. This is the smallest ALS-causing SOD1 molecule currently defined. This proof of principle result suggests that the exon-fusion approach may have potential not only to further define a shorter ALS-associated SOD1 fragment, thus providing a molecular target for designing rational therapy, but also to dissect toxicities of other proteins encoded by genes of multiple exons through a 'gain of function' mechanism.
  • Hirohide Asai; Fukashi Udaka; Makito Hirano; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 110 5 500 - 501 2008年05月 [査読有り]
    Odor is the only sensation thought to be unrelated to the thalamus. However, accumulating evidence suggests that the dorsomedial nucleus (DM) of the thalamus is associated with odor. Although the thalamus is prone to ischemia, only a single patient with bilateral DM infarctions was reported to have odor abnormalities. We describe a second such patient with infarctions involving the left DM and the right ventral posterior nucleus and ventral lateral nucleus, nuclei adjacent to the DM, associated with transient edema. In contrast to the previous case, our patient had transient odor abnormality. These observations suggested that direct and/or indirect bilateral involvement of the DM might be associated with odor abnormalities in patients with thalamic infarction. (c) 2008 Elsevier B.V. All rights reserved.
  • 小脳失調原因蛋白aprataxin導入によるTriple A症候群のストレス起因性細胞死の抑制
    平野 牧人; 降矢 芳子; 浅井 宏英; 桐山 敬生; 上野 聡
    臨床神経学 47 12 1120 - 1120 (一社)日本神経学会 2007年12月
  • ALADIN変異によるTriple A症候群における、小脳失調原因蛋白aprataxinの核内輸送障害
    浅井 宏英; 平野 牧人; 降矢 芳子; 桐山 敬生; 上野 聡
    臨床神経学 47 12 1120 - 1120 (一社)日本神経学会 2007年12月
  • 神経疾患におけるメタボリックシンドローム
    上野 聡; 降矢 芳子; 川原 誠; 杉江 和馬; 形岡 博史; 北内 誉敬; 桐山 敬生; 殿村 恭代; 谷掛 万里; 平野 牧人
    臨床神経学 47 12 1170 - 1170 (一社)日本神経学会 2007年12月
  • Megalencephalic leukoencephalopathy with subcortical cystsのMRI、SPECT所見の検討
    桐山 敬生; 平野 牧人; 谷澤 恵美; 浅井 宏英; 降矢 芳子; 上野 聡
    臨床神経学 47 12 1173 - 1173 (一社)日本神経学会 2007年12月
  • Yoshiko Furiya; Makito Hirano; Masami Nomura; Hirohide Asai; Takao Kiriyama; Satoshi Ueno
  • Toshiaki Taoka; Tesseki Kin; Hiroyuki Nakagawa; Makito Hirano; Masahiko Sakamoto; Takeshi Wada; Katsutoshi Takayama; Chatchada Wuttikul; Satoru Iwasaki; Satoshi Ueno; Kimihiko Kichikawa
    NEUROIMAGE 37 2 387 - 393 2007年08月 [査読有り]
    Purpose: This study accessed the feasibility of using tractography-based analysis to evaluate the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of three cerebellar peduncles in subtypes of spinocerebellar degenerative disease. Materials and methods: We examined 7 cases of dentatorubropallidoluysian atrophy (DRPLA), 4 cases of multiple system atrophy, cerebellar type (MSA-C), 4 cases of late cerebellar cortical atrophy (LCCA) and 8 controls. Diffusion tensor images were obtained, and tractographies of cerebellar peduncles were generated. ADC and FA along the cerebellar peduncles and volume of cerebellar peduncle were measured, and analyses of variance were made among the control and each spinocerebellar degenerative disease groups. Results: There were statistically significant decrease in FA and volume and increase in ADC values between DRPLA cases and controls in all three cerebellar peduncles. On the other hand, MSA-C cases mainly showed statistically significant decreased FA and volume and increased ADC values in the middle cerebellar peduncle. LCCA cases did not show prominent difference in the three cerebellar peduncles. Conclusion: The values of diffusivity and diffusion anisotropy of cerebellar peduncles evaluated by tractography based measurements seem to reflect characteristics of the different types of spinocerebellar degenerative diseases. Tractography- based measurements may be a feasible tool for differential diagnosis of spinocerebellar degenerative disease. (c) 2007 Elsevier Inc. All rights reserved.
  • Takao Kiriyama; Emi Tanizawa; Makito Hirano; Takayuki Shinkai; Hirohide Asai; Yoshiko Furiya; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 109 6 526 - 530 2007年07月 [査読有り]
    We describe the findings on single photon emission computed tomography (SPECT) in a patient who had genetically definite megalencephalic leukoencephalopathy with subcortical cysts. Technetium-99m-ethyl cysteinate dimer SPECT revealed hypoperfusion in the cerebral white matter, which had shown high signal intensity on magnetic resonance imaging (MRI) T2 images. Hypoperfusion was also unexpectedly found in the frontal cortices, which showed no abnormalities on MRI. This frontal abnormality corresponded clinically to a low score on the frontal assessment battery. Decreased GABA receptor density as suggested by I-123-Iomazenil SPECT provided further evidence of cortical neuron dysfunction. Although confirmation must await future larger-scale SPECT and functional studies, our findings suggest that SPECT can be used to non-invasively monitor in vivo cortical function in this disease. (C) 2007 Elsevier B.V. All rights reserved.
  • Makito Hirano; Hirohide Asai; Takao Kiriyama; Yoshiko Furiya; Takaaki Iwamoto; Tomohisa Nishiwaki; Aya Yamamoto; Toshio Mori; Satoshi Ueno
    NEUROSCIENCE LETTERS 419 2 184 - 187 2007年05月 [査読有り]
    Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is caused by mutations in the gene encoding aprataxin (APTX). Although several in vitro findings proposed that impaired enzymatic activities of APTX are responsible for EACH/AOA1, potential instability of mutant proteins has also been suggested as the pathogenesis based on in vivo finding that mutant proteins are almost undetectable in EAOR/AOA1 tissues or cells. The present study aimed to experimentally prove instability of mutant proteins in neuronal cells, the cell type preferentially affected by this disease. Results of pulse-chase experiments demonstrated that all of the disease-associated mutants had extremely shorter half-lives than the WT. We further found that mutants were targeted for rapid proteasome-mediated degradation. These results help establish pathogenic and physiological protein characteristics of APTX in neuronal cells. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Hisao Shimizu; Hiroshi Kataoka; Makoto Kawahara; Makito Hirano; Yoshiko Furiya; Satoshi Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 109 3 277 - 278 2007年04月 [査読有り]
    We describe a successful outcome of long-term interferon beta-1b therapy in a patient who had multiple sclerosis (MS) with positive serum autoantibody to muscle acetylcholine receptor (AChR-Ab). Because of the reported possible causative linkage between interferon beta-1b and myasthenia gravis (MG), the presence of the pathogenic antibody complicated therapeutic strategies. We carefully observed the patient for further 6 months before the treatment, excluding symptomatic MG. The interferon beta-1b therapy then provided a clinical benefit. Hopefully this report will allow MS patients in similar situations to make more rapid, unprejudiced judgments than our patients. (c) 2006 Elsevier B.V. All rights reserved.
  • Hirohide Asai; Makito Hirano; Fukashi Udaka; Keiji Shimada; Masaya Oda; Tamotsu Kubori; Kazuto Nishinaka; Takahiro Tsujimura; Yuishin Izumi; Noboru Konishi; Sadayuki Matsumoto; Masakuni Kameyama; Satoshi Ueno
    JOURNAL OF THE NEUROLOGICAL SCIENCES 254 1-2 78 - 83 2007年03月 [査読有り]
    Backgroung; ALS exclusively involves motor neurons, however, accumulating evidence suggests involvement of sympathetic neurons, as in other diseases including Parkinson's disease and multiple system atrophy. In these diseases increased risk of sudden cardiac arrest is established, while that in ALS remains uncertain. Methods: The authors retrospectively studied 12 pathologically confirmed sporadic ALS patients who received no assisted ventilation. Among them, two patients died of sudden cardiac arrest. Changes in QTc interval and dispersion, indices of sympathetic activities obtainable by routine electrocardiograms, were evaluated at the early stage and the terminal stage. Pathologically, intermediolateral nucleus (IML) sympathetic neurons in the upper thoracic cord were examined. Results: The QTc intervals and dispersion were significantly increased at the terminal stage compared with that at the early stage (p < 0.01). The numbers of IML neurons were significantly lower in ALS patients than in controls (p=0.017), and had linear inverse correlation with the rate of increases in maximum QTc interval and QTc dispersion (p=0.01, r=-0.915 and p=0.02, r=-0.884). Notably, two patients with sudden cardiac arrest showed longer QTc interval, larger QTc dispersion, and lower number of IML neurons than most of others. Conclusions: Patients with AILS had reduced sympathetic activities at the terminal stage of disease, presumably due to neuronal loss in IML, which may increase risk of sudden cardiac arrest. Thus, prolonged QTc intervals and increased QTc dispersion may suggest an increased risk of sudden death in AILS, as in other neurodegenerative diseases. (c) 2007 Elsevier B.V. All rights reserved.
  • Makito Hirano; Aya Yamamoto; Toshio Mori; Li Lan; Taka-aki Iwamoto; Masashi Aoki; Keiji Shimada; Yoshiko Furiya; Shingo Kariya; Hirohide Asai; Akira Yasui; Tomohisa Nishiwaki; Kyoko Imoto; Nobuhiko Kobayashi; Takao Kiriyama; Tetsuya Nagata; Noboru Konishi; Yasuto Itoyama; Satoshi Ueno
    ANNALS OF NEUROLOGY 61 2 162 - 174 2007年02月 [査読有り]
    Objective: Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type I (AOA1) is an autosomal recessive form of cerebellar ataxia. The causative protein for EAOH/AOA1, aprataxin (APTX), interacts with X-ray repair cross-complementing 1 (XRCC1), a scaffold DNA repair protein for single-strand breaks (SSBs). The goal of this study was to prove the functional involvement of APTX in SSB repair (SSBR). Methods: We visualized the SSBR process with a recently developed laser irradiation system that allows real-time observation of SSBR proteins and with a local ultraviolet-irradiation system using a XPA-UVDE cell line that repairs DNA lesions exclusively via SSBR. APTX was knocked down using small interference RNA in the cells. Oxidative stress-induced DNA damage and cell death were assessed in EAOH fibroblasts and cerebellum. Results: Our systems showed the XRCC1-dependent recruitment of APTX to SSBs. SSBR was impaired in APTX-knocked-down cells. Oxidative stress in EAOH fibroblasts readily induced SSBs and cell death, which were blocked by antioxidants. Accumulated oxidative DNA damage was confirmed in EAOH cerebellum. Interpretation: This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.
  • Miyuki Kajitani; Hajime Yagura; Makoto Kawahara; Makito Hirano; Satoshi Ueno; Kenta Fujimoto; Toshisuke Sakaki; Toshiaki Taoka; Hiroyuki Nakagawa; Kimihiko Kichikawa
    MOVEMENT DISORDERS 22 3 437 - 439 2007年02月 [査読有り]
  • 常染色体優性遺伝脊髄小脳変性症におけるpuratropin-1遺伝子変異の検討
    降矢 芳子; 平野 牧人; 浅井 宏英; 桐山 敬生; 上野 聡
    臨床神経学 46 12 1019 - 1019 (一社)日本神経学会 2006年12月
  • 新しいALADIN遺伝子変異(I482S)を認めたtriple A症候群の1家系
    平野 牧人; 金 哲石; 清水 久央; 形岡 博史; 降矢 芳子; 浅井 宏英; 桐山 敬生; 上野 聡
    臨床神経学 46 8 595 - 595 (一社)日本神経学会 2006年08月
  • M Takamure; M Hirano; T Taoka; S Ueno
    CLINICAL NEUROLOGY AND NEUROSURGERY 108 5 482 - 485 2006年07月 [査読有り]
    Serial T2-weighted magnetic resonance imaging in a 29-year-old woman with juvenile type dentatorubral-pallidoluysian atrophy (DRPLA) demonstrated that a cerebral white matter hyperintensity appeared within 2 months after status epilepticus and persisted for more than 20 months. The patient had rapidly progressive mental regression and became akinetic after status epilepticus. The chronological relationship between the signal changes and the clinical deterioration suggested that the epilepsy, at least in part, contributed to the progression of white matter degeneration, the hallmark of DRPLA. (c) 2005 Elsevier B.V. All rights reserved.
  • Tesseki Kin; Kazuma Sugie; Makito Hirano; Yu-ichi Goto; Ichizo Nishino; Satoshi Ueno
    JOURNAL OF HUMAN GENETICS 51 6 555 - 558 2006年06月 [査読有り]
    We showed that humanin (HN), an endogenous peptide against Alzheimer disease-related insults, was expressed in muscles of patients with chronic progressive external ophthalmoplegia (CPEO), a major mitochondrial disease. Because HN was recently found to block proapoptotic Bax function and exert its versatile cytoprotective effects in association with an increase in ATP levels, HN expression may thus reflect a physiological response against degenerative changes in the muscles of patients with CPEO. We found HN expression in all four patients examined, each of whom had different mitochondrial DNA mutations including two different single DNA deletions, multiple deletions, and no major mutations detected. We also found that HN expression was not linked to focal cytochrome c deficiency, strongly associated with the subtype of CPEO with single deletions. These results suggest that HN expression is more closely related to degenerative changes in all types of CPEO. Notably, HN was also expressed in non-degenerative muscle fibers of patients with CPEO or Leigh syndrome, who had the 8993T > G mutation in the mitochondrial ATPase 6 gene known to be associated with impaired ATP synthesis. Collectively, our findings suggest that HN may be specifically expressed in response to defects in energy production in muscles with mitochondrial abnormalities.
  • Yoshiko Furiya; Makito Hirano; Takuya Nakamuro; Hiroshi Kataoka; Satoshi Ueno
    Journal of Infection 52 5 e143 - e146 2006年05月 [査読有り]
    Japanese encephalitis (JE) virus is a mosquito-borne virus belonging to the flavivirus family, including the West Nile and St Louis encephalitis viruses endemic to North America. JE virus is prevalent in East Asian countries and can cause acute lethal encephalitis. Although vaccination programs have decreased the incidence of JE in Japan, the cases that do occur are often fatal or associated with considerable clinical sequelae. We report, for the first time to our knowledge, a patient who had repetitive bouts of hyperthermia in the summertime after recovery from acute JE. An insulin challenge test revealed only marginal increases in the levels of β-endorphin and growth hormone, indicating partial medial hypothalamic dysfunction. Magnetic resonance imaging showed T2 hyperintensity in both thalamic paraventricular subcortical regions, known to project to the hypothalamic paraventricular nucleus. We thus attributed the episodes of hyperthermia to secondary hypothalamic impairment with thalamic lesions. © 2005 The British Infection Society.
  • M Hirano; Y Furiya; H Asai; A Yasui; S Ueno
    Triple A syndrome is an autosomal recessive neuroendocrinological disease caused by mutations in a gene that encodes 546 amino acid residues. The encoded protein is the nucleoporin ALADIN, a component of nuclear pore complex (NPC). We identified a mutant ALADIN(1482S) that fails to target NPC and investigated the consequences of mistargeting using cultured fibroblasts (1482Sf) from a patient with triple A syndrome. ALADIN(1482s) affected a katyopherin-alpha/beta-mediated import pathway and decreased nuclear accumulations of aprataxin (APTX), a repair protein for DNA single-strand breaks (SSBs), and of DNA ligase I in 1482Sf. This decrease was restored by wild-type ALADIN. ALADIN1482s had no effect on imports of M9/kap-beta 2, BIB/kap-beta 3, histone H1/importin 7, the ubiquitin conjugating enzyme UbcM2/importin 11, or the spliceo-some protein U1A, indicating that ALADIN1482S selectively impaired transport of discrete import complexes through NPC. Cell survival assay showed hypersensitivity of 1482Sf to L-buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent. BSO decreased nuclear APTX and ligase I levels in 1482Sf and normal control fibroblasts, but increased SSBs only in 1482Sf. These observations implied that 1482Sf are hypersensitive to BSO and no longer sufficiently repair SSBs. Consistent with this notion, 1482Sf transfected with both APTX and ligase I had increased resistance to BSO, whereas 1482Sf transfected with LacZ vector remained hypersensitive to BSO. We propose that oxidative stress aggravates nuclear import failure, which is already compromised in patient cells. Consequent DNA damage, beyond the limited capacity of DNA repair proteins, i.e., APTX and ligase 1, may participate in triggering cell death.
  • S Kariya; M Hirano; S Uesato; Y Nagai; Y Nagaoka; Y Furiya; H Asai; N Fujikake; T Toda; S Ueno
    NEUROSCIENCE LETTERS 392 3 213 - 215 2006年01月 [査読有り]
    Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurological disorder caused by a CAG repeat expansion in the DRPLA gene encoding polyglutamine, (polyQ). Although previous experimental studies have demonstrated that histone deacetylase (HDAC) inhibitors are therapeutically active, known HDAC inhibitors have considerable adverse effects clinically. To identify new HDAC inhibitors for the treatment of DRPLA, we evaluated a new series of HDAC inhibitors, N-hydroxycarboxamides des, with our drug screening system, which uses neuronal PC12 cells stably transfected with a part of the DRPLA gene. We found that two of four N-hydroxycarboxamides significantly reduced polyQ-induced cell death. The essential structure of these compounds is a hydroxamic acid residue, which is shared with trichostatin A, a known HDAC inhibitor. Although our study showed mild neuroprotective effects, further structural modification of compounds that retain this residue may decrease cytotoxicity and increase protective activity against polyQ toxicity. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
  • Y Furiya; M Hirano; N Kurumatani; T Nakamuro; R Matsumura; N Futamura; S Ueno
    MOLECULAR BRAIN RESEARCH 138 2 178 - 181 2005年08月 [査読有り]
    We investigated three genotypes (AA, AT, and TT) produced by signal peptide polymorphism of the alpha-1-antichymottypsin (ACT) gene in 105 patients with multiple system atrophy (MSA) and age-matched controls. The frequency of ACT-AA genotype was significantly higher in patients with MSA (20.0%) than in controls (10.5%). The onset of MSA was significantly earlier and the disease progressed significantly faster in patients with ACT-AA genotype than in those with non-ACT-AA genotypes. The ACT concentration in cerebrospinal fluid was increased in patients with ACT-AA. To our knowledge, this is the first study to show that the ACT-AA genotype is a risk factor and modulating factor for MSA. Our findings suggest the involvement of ACT-relating inflammatory process in the pathogenesis of MSA. (c) 2005 Elsevier B.V. All rights reserved.
  • S Kariya; M Hirano; N Takahashi; Y Furiya; S Ueno
    JOURNAL OF THE NEUROLOGICAL SCIENCES 232 1-2 91 - 94 2005年05月 [査読有り]
    The etiology of Parkinson's disease (PD) remains unclear; however, generation of reactive oxygen species during oxidation of dopamine (DA) could be one of the factors leading to selective loss of nigral dopaminergic neurons in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake and partition DA from neuronal cytoplasm into synaptic vesicles. Therefore, alterations of VMAT2 function may cause cytoplasmic accumulation of free DA, toxic to dopaminergic neurons. Upstream of a putative promoter region of the VMAT2 gene, there exist polymorphic sequences consisting of two microsatellites, (CA)(n) and (GA)(n). We performed a case-control study of this polymorphic region to determine whether the VMAT2 gene is related to PD. We found six genotypes; however, there was no significant difference in the allele frequencies between patients with PD and control subjects. Our data suggest that the polymorphic region of the VMAT2 gene studied here is not closely related to PD. © 2005 Elsevier B.V. All rights reserved.
  • S Kariya; M Hirano; Y Furiya; S Ueno
    NEUROPEPTIDES 39 2 97 - 101 2005年04月 [査読有り]
    Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS. (c) 2005 Elsevier Ltd. All rights reserved.
  • S Kariya; M Hirano; Y Furiya; K Sugie; S Ueno
    ACTA NEUROPATHOLOGICA 109 4 367 - 372 2005年04月 [査読有り]
    Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis induced by various types of Alzheimers disease-related insults. We have previously indicated that HN increases cellular ATP levels and speculated that this peptide may rescue energy-deficient cells in mitochondrial disorders. Here, we report, for the first time, increased HN expression in skeletal muscles from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). HN was strongly positive in all ragged-red fibers (RRFs) and some non-RRFs, and most of them were type 1 fibers generally requiring higher energy than type 2 fibers. HN in these fibers was localized in mitochondria. HN expression was also increased in small arteries that strongly reacted for succinate dehydrogenase. Our experiments on muscular TE671 cells indicated the possibility that synthesized HN increases cellular ATP levels by directly acting on mitochondria. From these in vivo and in vitro findings, we propose that HN expression might be induced in response to the energy crisis within affected fibers and vessels in MELAS muscles and further be a possible therapeutic candidate for MELAS.
  • S Kariya; M Hirano; Y Nagai; Y Furiya; N Fujikake; T Toda; S Uenol
    JOURNAL OF MOLECULAR NEUROSCIENCE 25 2 165 - 169 2005年 [査読有り]
    Dentatorubral-pallidoluysianatrophy (DRPLA) is an autosomal-dominantneurodegenerative disorder caused by expansion of CAG repeats in the DRPLA gene, which codes for a polyglutamine (polyQ) stretch. The expanded polyQs are known to form intracellular aggregates and to confer neurotoxic activity. Recent studies have indicated that activation of apoptosis signal-regulating kinase 1 (ASK1) is involved in polyQ-induced apoptosis. Humanin (HN) is an endogenous peptide that inhibits neuronal cell death caused by mutant Alzheimer's disease genes, and this neuroprotective factor has recently been reported to suppress apoptosis by inhibiting activation of ASK1. To test the anti-ASK1 effect of HN on polyQ neurotoxicity, we constructed neuronal PC12 cells expressing expanded polyQs under the control of the Tet-Off™ system. Using this cell line, we showed that HN suppresses apoptotic cell death induced by expanded polyQs. However, the suppression was incomplete, suggesting that polyQs also stimulate other pathogenic cascades unrelated to ASK1. We further showed that HN suppresses polyQ aggregate formation. This result implied the possibility that aggregation is also related to the polyQ-mediated cascade involving ASK1 activation. Although the details remain uncertain, our results suggest that ASK1 is potentially involved in pathogenesis of DRPLA and that HN might contribute partially to the suppression of neurodegeneration in polyQ diseases.
  • Tesseki Kin; Makito Hirano; Toshiaki Taoka; Miwa Takamure; Yoshiko Furiya; Kimihiko Kichikawa; Satoshi Ueno
    Magnetic Resonance in Medical Sciences 4 3 123 - 127 2005年 [査読有り]
    Purpose: To quantify impairment of the basal ganglia (globus pallidus and thalamus) in adult-onset dentatorubral-pallidoluysian atrophy (DRPLA). Methods: Five patients with genetically definite adult-onset DRPLA (aged 51 to 65 years, mean 55.6 years) and 5 age- and sex-matched healthy controls underwent conventional magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) of the brain in the voxels predominantly containing the globus pallidus or the thalamus. Results: Conventional MRI studies showed apparently normal intensities in the globus pallidus and thalamus. MRS showed that the choline (Cho)/creatine (Cr) ratio for the patients' globus pallidus, the region preferentially affected in DRPLA, was significantly higher than that in the controls (p< 0.05). The N-acetylaspartate (NAA)/Cr ratio for the globus pallidus and the Cho/Cr and NAA/Cr ratios for the thalamus, the region relatively spared in this disease, did not differ significantly between the patients and controls. Conclusions: MRS may sensitively and specifically detect biochemical alterations in susceptible regions of patients with adult-onset DRPLA.
  • S Kariya; N Takahashi; M Hirano; S Ueno
    JOURNAL OF MOLECULAR NEUROSCIENCE 27 3 277 - 279 2005年 [査読有り]
    Parkinson's disease (PD) is characterized by a preferential loss of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD remains unclear; however, generation of reactive oxygen species during oxidation of free dopamine (DA) in the cytoplasm might be one of the causes of selective dopaminergic neuron loss in PD. Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals take up and partition DA from neuronal cytoplasm into synaptic vesicles. Alterations of VMAT2 function might therefore cause cytoplasmic accumulation of free DA, which is toxic for dopaminergic neurons. We showed that dopaminergic neurons from VMAT2 heterozygous knockout mice were more vulnerable to the toxic effect Of L-3,4-dihydroxyphenylalanine (L-DOPA, a DA precursor) than those from wild-type mice. Our results suggest that reduction of VMAT2 activity might attenuate the efficacy Of L-DOPA therapy for patients with PD.
  • H Asai; F Udaka; M Hirano; T Minami; M Oda; T Kubori; K Nishinaka; M Kameyama; S Ueno
    PARKINSONISM & RELATED DISORDERS 11 8 499 - 502 2005年 [査読有り]
    We investigated the clinical efficacy and tolerability of 45 mg/day mosapride, a selective 5-hydroxytryptamine type 4 (5-HT4) agonist, in an open-label study involving five patients with Parkinson's disease (PD) who had response fluctuations (RFs). 'On' time and motor function scores were determined, and gastric motility was measured by a radionuclide gastric emptying (GE) test, the most reliable quantitative method available. We found that mosapride therapy significantly shortened GE half-time, reduced RFs, and improved motor functions in all patients. There were no adverse reactions. We conclude that selective 5-HT4 agonist therapy is beneficial for patients with PD who have RFs. (c) 2005 Elsevier Ltd. All rights reserved.
  • M Hirano; Y Furiya; S Kariya; T Nishiwaki; S Ueno
    Early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is an autosomal recessive form of cerebellar ataxia that occurs most commonly in Japan but is also frequently seen in Europe. This disease is caused by mutations in the aprataxin gene, but the functions of the gene product and the pathogenic mechanism remain unclear. The present study provides experimental evidence that the histidine triad (HIT) domain in aprataxin has enzymatic activity that is negatively regulated by the intramolecular interaction of the N-terminal domain. Furthermore, the reduction in HIT activity seen in all the disease-causing mutants tested, and the correlation between the reduced activity and the severe phenotype, support that aprataxin's physiological function is associated with its catalytic activity. Our findings suggest that the clinical phenotypes are caused by a loss of aprataxin function, attributable largely to diminished HIT activity but partially to a reduction in the levels of gene products. (C) 2004 Elsevier Inc. All rights reserved.
  • M Hirano; T Nishiwaki; S Kariya; Y Furiya; M Kawahara; S Ueno
    NEUROSCIENCE LETTERS 366 2 120 - 125 2004年08月 [査読有り]
    Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is one of the most common forms of autosomal recessive cerebellar ataxia. We identified six new alternative transcripts produced by the aprataxin gene responsible for EAOH Total eight transcripts encoded truncated proteins that were located within the nucleus or cytoplasm and showed different binding abilities to wild-type (WT) aprataxin. Thus, the alternative splicing increases the molecular diversity of aprataxin and the expression profiles of these transcripts in various tissues may be related to the tissue-specific phenotypes. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • S Kariya; N Takahashi; M Hirano; S Ueno
    MOLECULAR AND CELLULAR BIOCHEMISTRY 254 1-2 83 - 89 2003年12月 [査読有り]
    Humanin (HN) has been reported to be an endogenous peptide that exerts highly selective neuroprotection against cell death induced by various types of Alzheimer's disease-related insults. We previously proposed the much broader cytoprotective potential of HN from the result that HN suppressed serum-deprivation-induced death of rat pheochromocytoma cells. In this study, we showed that HN also suppressed death of human lymphocytes cultured under serum-deprived condition. Further, we revealed, by assaying metabolic activity and survival rate, that HN was a potent factor capable of increasing the metabolic activity of individual serum-deprived lymphocytes. To our knowledge, there is no report described about a rescue factor that increases the metabolic activity of individual serum-deprived cells and prolongs their survival. This novel feature of HN may enable us to apply this peptide for the management of diseases involving poor metabolic activity, such as mitochondria-related disorders and brain ischemia.
  • N Takahashi; S Kariya; M Hirano; S Ueno
    MOLECULAR AND CELLULAR BIOCHEMISTRY 252 1-2 279 - 283 2003年10月 [査読有り]
    We identified two novel spliced human presenilin 2 (PS2) transcripts. The first, PS2DeltaEx3-7, lacked part of exon 3, all of exons 4, 5, and 6, and part of exon 7, resulting in an in-frame shift and inclusion of the natural start codon and proteolytic region. This transcript was detected in cerebral cortex and peripheral lymphocytes. The second transcript, PS2DeltaEx4, lacked exon 4, resulting in a frame shift and inclusion of the natural start codon, and was transcribed in peripheral lymphocytes and heart but not in brain. Quantitative RT-PCR analysis revealed that the PS2DeltaEx3 - 7 significantly increased in lymphocytes treated with H2O2, suggesting that this transcript is a novel genetic marker that can be used to study the pathogenesis of Alzheimer's disease.
  • M. Hirano; S. Kusunoki; H. Asai; Y. Tonomura; D. Morita; Satoshi Ueno
    Neurology 60 1719 - 1720 2003年05月
  • Y. Yang; A. Hentati; H. X. Deng; O. Dabbagh; T. Sasaki; M. Hirano; W. Y. Hung; K. Ouahchi; J. Yan; A. C. Azim; N. Cole; G. Gascon; A. Yagmour; M. Ben-Hamida; M. Pericak-Vance; F. Hentati; T. Siddique
    Nature Genetics 29 2001年12月
  • Y Yang; A Hentati; HX Deng; O Dabbagh; T Sasaki; M Hirano; WY Hung; K Ouahchi; JH Yan; AC Azim; N Cole; G Gascon; A Yagmour; M Ben-Hamida; M Pericak-Vance; F Hentati; T Siddique
    NATURE GENETICS 29 2 160 - 165 2001年10月 
    Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).
  • Gaudette Mara; Makito Hirano; Teepu Siddique; Teepu Siddique
    Amyotrophic Lateral Sclerosis 1 83 - 89 2000年12月 
    Twenty percent of cases of familial amyotrophic lateral sclerosis (FALS) have identifiable mutations in the gene for Cu,Zn superoxide dismutase (SOD1) located on the long arm of chromosome 21. SOD1 mutations are thought to cause a yet unknown toxic gain of function resulting in motor neuron damage. Seventy-one mutations, located in all five exons of SOD1, have been reported. Identified mutations are predominantly heterozygous mis-sense mutations, although rare nonsense mutations, deletions, and insertions exist. While gene dosage has an effect on the age of onset, genotoype/phenotype correlation is better defined for progression of symptoms than for disease onset. (ALS 2000; 1:83-89) © 2000 Informa UK Ltd All rights reserved.
  • M Hirano; WY Hung; N Cole; AC Azim; HX Deng; T Siddique
    We have identified five alternatively spliced transcripts of the gene for human Cu,Zn superoxide dismutase (SOD1), a causative gene for autosomal dominant amyotrophic lateral sclerosis (ALS). The splice variants of wild-type or mutant SOD1 were expressed in a tissue-specific manner; therefore, their expression may be regulated to modify SOD1 function. In addition, the expression in the brain implies that variants may play a role in the nervous system, the region involved in ALS. Immunoblot study of HeLa cells transfected with two variants encoding C-terminal truncated proteins did not show the proteins of expected size. However, this observation is consistent with the previous study of C-terminal truncated mutant proteins that cause ALS, suggesting that both variant and mutant proteins may share certain properties, such as instability or insolubility in the cytosol. These findings suggest that the splice variants may contribute to a physiological function of SOD1 or to a pathological mechanism in ALS. (C) 2000 Academic Press.
  • Satoshi Ueno; Makito Hirano
    Brain and Development 22 2000年09月 
    Hereditary progressive dystonia (HPD) with marked diurnal fluctuation is caused by mutant guanosine triphosphate (GTP) cyclohydrolase I (GCH). The clinical presentation of dominant HPD varies considerably. We proposed the hypothesis that a relative increase of mutant GCH capable of inhibiting normal GCH is responsible for heterogeneous phenotypic manifestations. In a Japanese family with a novel G90V mutation, an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Co-expression analysis showed that mutant enzyme (GCH-G90V) inactivated the normal enzyme in the COS cells. Similarly, GCH-G203R showed the dominant negative effects. These results supported our proposed hypothesis. Copyright (C) 2000 Elsevier Science B.V.
  • Mayumi Yoshikawa; Mayumi Yoshikawa; Hitoshi Nakayama; Satoshi Ueno; Makito Hirano; Hiroshi Hatanaka; Hitoshi Furuya
    Brain Research 859 2 217 - 223 2000年03月 
    Chronic activation of adenylate cyclase-cAMP-cAMP-dependent protein kinase (PKA) systems by administration of opioid receptor agonists has been considered as one of the mechanisms of opioid tolerance and dependence. Although analysis of the μ opioid receptor (MOR) gene suggests that cAMP-related signal transduction systems regulate the expression of this gene, which transcription factors affect the MOR gene expression in brain and neural cells has not been clarified. This study deals with the effects of fentanyl on MOR mRNA levels in the rat pheochromocytoma cell line (PC12 cells). PC12 cells were cultured in medium with clinically relevant concentrations of fentanyl. The quantitative reverse transcription and polymerase chain reaction (RT-PCR) method was used for determination of MOR mRNA. Treatment of PC12 cells with fentanyl induced the MOR mRNA up-regulation in a concentration- and time-dependent manner. A cAMP analogue also up-regulated MOR mRNA. The intracellular cAMP level increased after fentanyl treatment. A PKA inhibitor blocked the MOR mRNA up-regulation by fentanyl and the cAMP analogue. Expression of a dominant inhibitory Ras also inhibited the MOR mRNA up-regulation. Fentanyl-induced up-regulation of MOR mRNA via activation of cAMP signaling may be important in compensating for the MOR reduction during long-term treatment of PC12 cells with fentanyl. The present study could be relevant to understanding the molecular mechanisms of opioids in a state of drug tolerance or dependence, and in patients under anesthesia or being treated for pain. Copyright (C) 2000 Elsevier Science B.V.
  • M Gaudette; M Hirano; T Siddique
    Twenty percent of cases of familial amyotrophic lateral sclerosis (FALS) have identifiable mutations in the gene for Cu,Zn superoxide dismutase (SOD1) located on the long arm of chromosome 21. SOD1 mutations are thought to cause a yet unknown toxic gain of function resulting in motor neuron damage. Seventy-one mutations, located in all five exons of SOD1, have been reported, Identified mutations are predominantly heterozygous mis-sense mutations, although rare nonsense mutations, deletions, and insertions exist. While gene dosage has an effect on the age of onset, genotoype/phenotype correlation is better defined for progression of symptoms than for disease onset.
  • K Hayakawa; M Hirano; K Yoshikawa; N Katsumata; T Tanaka
    JOURNAL OF CHROMATOGRAPHY A 846 1-2 73 - 82 1999年06月 [査読有り]
    A unique. but general, separation method of phenylthiohydantoin (PTH)-amino acids has been devised by using a temperature-controlled gradient-elution mode of reversed-phase high-performance liquid chromatography. The gradient was established from two solvents (A* and B*) which consisted of an aqueous acidic phosphate buffer solution (pH 2.1, 0.1 M) and alcoholic organic modifiers, which afforded stable analysis. The column used was Develosil ODS UG-5. The addition of acetonitrile to solvent B* and running the column at a higher temperature was essential for separating PTH-valine and 1,3-diphenyl-2-thiourea. It was found that separation of the early-eluting solvophilic amino acids was more efficient at lower column temperatures, but that a higher temperature was required for separating PTH-methionine from PTH-valine, using a 60 Angstrom pore diameter ODS silica as model gel. Therefore, temperature control from 35 to 60 degrees C was introduced. Since this separation method is reproducible, convenient, and quantitative, it was applied to the yield analysis of bovine P-lactoglobulin and several peptides after covalent bonding to glass fiber disks. (C) 1999 Elsevier Science B.V. All rights reserved.
  • Makito Hirano; Osamu Komure; Satoshi Ueno
    Neuroscience Letters 260 181 - 184 1999年02月 
    Dopa-responsive dystonia (DRD) due to mutant GTP cyclohydrolase I (GCH) shows the considerable heterogeneity of clinical phenotypic expression. To explain the clinical diversity, we studied a Japanese family with a novel mutant GCH (GCH-G90V), where an affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote. Coexpression experiments using the mutant with wild-type GCH showed that GCH-G90V inactivated the normal enzyme in a dose-dependent manner, suggesting that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms for the clinical heterogeneity of DRD.
  • Mayumi Yoshikawa; Satoshi Ueno; Makito Hirano; Hitoshi Nakayama; Hitoshi Furuya
    Pharmacy and Pharmacology Communications 5 10 603 - 607 1999年 
    The effect of fentanyl, an opioid receptor agonist, on the survival of a rat pheochromocytoma cell line (PC12 cells) after serum deprivation was studied. PCR amplification of reverse-transcribed mRNA demonstrated the μ-opioid receptor transcripts in the PC12 cells. The metabolism of a tetrazolium dye (MTS) assay showed that cell viability was significantly reduced, and agarose electrophoresis of the DNA extracted from the cells resulted in a ladder-like pattern of fragmentation 18 h after serum withdrawal. The incubation with fentanyl prolonged cell survival in a dose-dependent manner. This effect was abolished by naloxone. There was a rapid and transient induction of the c-fos, c-jun and heat shock protein 70 genes, in PC12 cells after serum deprivation, which was not observed in fentanyl-treated PC12 cells.
  • M Hirano; S Ueno
    NEUROLOGY 52 1 182 - 184 1999年01月 
    Guanosine 5'-triphosphate cyclohydrolase I (GCH) mutants (H144P and T186K) associated with dominant dopa-responsive dystonia were enzymatically inactive and inhibited the normal enzyme, suggesting that GCH activity in a heterozygote was <50% of control. The M211I mutant associated with recessive hyperphenylalaninemia was slightly active and had no inhibitory effects, so GCH activity in a heterozygote would be <50% of normal; therefore hyperphenylalaninemia would be evident only in homozygotes.
  • M Hirano; T Yanagihara; S Ueno
    ANNALS OF NEUROLOGY 44 3 365 - 371 1998年09月 
    Hereditary progressive dystonia (HPD) is caused by the mutant gene encoding GTP cyclohydrolase I (GCH). The clinical presentation of this disease varies considerably, and many cases appear to be sporadic. We have previously proposed that this clinical variation may be due to differential expression of the mutant and normal GCH mRNA, presumably at the protein level. To provide support for this proposal, we studied a new Japanese family with HPD, in which 2 members were heterozygous for an exon-skipping mutation. This mutation produced truncated GCH, which shared 180-amino acid residues at the amino terminus of the normal enzyme (GCH180). An affected heterozygote had a higher mutant/normal mRNA ratio than an unaffected heterozygote, consistent with our previous finding in the HPD family with GCH114, A further study, using coexpression of the mutant with wild-type GCH in COS-7 cells, showed that three mutant GCHs inactivated the normal enzyme. GCH114 was most effective in enzyme inactivation, which was followed by GCH180 and a normally occurring mutant GCH209. These results suggested that the dominant negative effect of a mutant GCH on the normal enzyme might be one of the molecular mechanisms determining the heterogeneity of clinical phenotypes of HPD.
  • Y Nagai; T Azuma; M Funauchi; M Fujita; M Umi; M Hirano; T Matsubara; S Ueno
    JOURNAL OF THE NEUROLOGICAL SCIENCES 157 1 52 - 59 1998年04月 
    We report on seven Japanese families with spinocerebellar ataxia type 6 (SCA6) carrying small CAG repeat expansions in the calcium channel alpha 1A subunit gene. The number of the expanded CAG repeat, ranged from 22 to 25, showed no intergenerational instability and had a significant inverse correlation with the age of onset. The clinical features of these patients were late onset progressive pure cerebellar ataxia with dysarthria and nystagmus, and are consistent with autosomal dominant cerebellar ataxia type III (ADCA type III). Magnetic resonance imaging scan of the brain demonstrated cerebellar atrophy with no evidence of brainstem involvement. We propose that clinical phenotype of SCA6 is compatible with ADCA type III and SCA6 is one of the most common types of ADCA in Japan. (C) 1998 Elsevier Science B.V.
  • Y Tamaru; M Hirano; H Ito; J Kawamura; S Matsumoto; T Imai; S Ueno
    Objective-Hereditary progressive dystonia with pronounced diurnal fluctuation ((HPD)/dopa responsive dystonia (DRD)) is a childhood onset dystonia which responds to levodopa. Various clinical si,sns and symptoms of HPD/DRD have been recognised to date. Mutations in the GTP cyclohydrolase I (GTP-CH-I) gene were recently identified as the cause of HPD/DRD. In the present study, the GTP-CH-I gene and the clinical features of eight HPD/DRD patients from six families were analysed to determine the correlations between clinical expression and the mutations in the GTP-CH-I gene. Methods-The exons, exon-intron junctions, and an indispensable part of the 5' flanking region of the GTP-CH-I gene were sequenced in the eight clinically diagnosed patients with HPD/DRD and their asymptomatic parents. Results-Three independent mutations in the GTP-CH-I gene were found in three patients. One of the patients and her asymptomatic mother were heterozygous for a novel mutation art the initiation codon. The three patients with dissimilar GTP-CH-I mutations exhibited similar clinical features. The other five patients with normal sequences presented several features not manifested by the three patients with the mutations. No mutation was found in the 5' flanking region of any patients or their parents. Conclusions-A novel initiation codon mutation was found in a Japanese patient with HPD/DRD. The clinical manifestations common to the patients with HPD. DRD with a mutated GTP-CH-I gene were also identified. Although focal manifestations of HPD/DRD associated with the mutations of this gene will be broadened, it is inferred that these clinical features are fundamental to HPD/DRD caused by mutations in this gene.
  • Y Imaiso; T Taniwaki; T Yamada; T Yoshimura; M Hirano; S Ueno; N Kaneda; J Kira
    NEUROLOGY 50 2 517 - 519 1998年02月 
    We report a 37-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuation and dopa-responsive dystonia. She developed dystonia in the lower limbs at the age of 11 years, followed by spasmodic torticollis and resting tremor of the feet, which responded remarkably to low doses of levodopa (100 mg/day). Concentrations of biopterin and neopterin in CSF were decreased. Polymerase chain reaction analysis of the guanosine 5'-triphosphate cyclohydrolase I gene revealed a novel mutation (Thr186-->Lys).
  • Y. Tamaru; Y. Tamaru; M. Hirano; M. Hirano; H. Kusaka; H. Ito; T. Imai; S. Ueno; S. Ueno
    Neurology 49 2 584 - 588 1997年08月 
    This report concerns the characterization of the α-tocopherol transfer protein (α-TTP) gene in a Japanese family affected by ataxia with isolated vitamin E deficiency (AVED). The sequence analysis revealed a G-to-A transition at the 3' end of exon 3 in both alleles, which predicts outsplicing of this exon from premessenger RNA and the concomitant frame shift in the ataxic patient. We used reverse transcriptase-polymerase chain reaction to analyze α-TTP gene transcripts. All transcripts in peripheral blood lymphocytes of the AVED patient, who was treated with large doses of vitamin E, lacked exon 3. The deduced truncated protein shares only 43% of the normal α-TTP. Normal control tissues and cells contained normal transcripts and, unexpectedly, also the same mutant transcripts as those of the patient, although with different transcription levels. Treatment of normal fibroblasts with clinically relevant concentrations of vitamin E increased production of transcripts in a dose-dependent manner. We propose that exon skipping of all transcripts through the complete inactivation of the splice site accounts for the clinical onset of AVED and for the clinical resistance to vitamin E in our patient.
  • M Hirano; Y Imaiso; S Ueno
    We characterized the GTP cyclohydrolase I (GTP-CH-I) gene in a patient with hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia (HPD/DRD). The sequence analysis revealed a C to A transversion, which predicts a novel missense mutation (Thr186Lys). Unexpectedly, this base change, occurring in the middle of exon 5, resulted in a production of the novel transcript lacking exon 5 and a part of exon 6. Three different transcripts of the GTP-CH-I gene, previously reported in the human liver, were also present in the peripheral lymphocytes from the patient and controls. quantitative comparison of the truncated-subunit mRNA and the wildtype one implied that differential splicing regulates the GTP-CH-I enzyme activity, leading to the clinical variations in HPD/DRD. The patient showed a unique clinical symptom, suggesting that the nigrostriatal dopaminergic system is more affected than previously thought in HPD/DRD. (C) 1997 Academic Press.
  • Y. Tamaru; H. Ito; T. Imai; M. Hirano; S. Ueno
    Nippon rinsho. Japanese journal of clinical medicine 55 135 - 138 1997年01月 
    Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a disorder characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. Recently the GTP cyclohydrolase I(GCH-I) gene was isolated as the first causative gene for HPD. We analyzed the GCH-I gene in 8 clinically diagnosed HPD patients and found different point mutations in GCH-I gene in 3 subjects. The clinical features of these patients considerably resembled each other. Our results imply that although clinically diagnosed HPD subjects could present diverse symptoms, patients with a mutant GCH-I gene might share homogeneous clinical manifestations.
  • α-Tocopherol Transfer Protein Gene: Exon Skipping of All Transcripts Causes Ataxia. Tmaru, Y.,Hrano, M., Kusaka, H., Ito, H., Imai, T., Ueno, S.
    Neurology 49, 584-588 1997年
  • M Iwano; S Ueno; M Miyazaki; T Harada; Y Nagai; M Hirano; Y Dohi; Y Akai; H Kurioka; K Dohi
    A gene has been identified by mRNA differential display whose expression is reduced in the renal cortex of MRL/lpr mouse. The nucleotide sequence of the cDNA contains an open reading frame that encodes a protein of 338 amino acids (termed LN1). In situ hybridization showed that LN1 mRNA is present in glomeruli, and a 39 kDa protein was detected in the kidney by immunoblot. A human LN1 cDNA was also isolated, the deduced amino acid sequence of which is 78% identical to that of mouse LN1. Although the function of LN1 remains to be elucidated, its reduced expression may contribute to the pathogenesis Of lupus nephritis. (C) 1996 Academic Press, Inc.
  • R Matsumura; T Takayanagi; K Murata; N Futamura; M Hirano; S Ueno
    HUMAN GENETICS 98 6 643 - 645 1996年12月 
    The mutation responsible for Machado-Joseph disease (MJD) has been identified as an expansion of a CAG trinucleotide repeat in a novel gene on chromosome 14q32.1. The CAG repeat tract is followed by C or G, and alleles are thereby divided into two types on the basis of molecular configuration, (CAG)nC and (CAG)nG, We have studied the relationship between the repeat length and the configuration in 38 patients from 28 Japanese families with MJD, and 31 unrelated normal Japanese subjects. The CAG repeat length in 100 normal alleles ranged from 13 to 37 repeats, while 38 MJD patients had one expanded allele with 64 to 84 repeats, Surprisingly, the expanded alleles had exclusively the (CAG)nC configuration, while both (CAG)nC and (CAG)nG were seen in normal alleles from MJD and control subjects. Furthermore, in normal alleles, the CAG repeat tract was significantly longer in (CAG)nC than in (CAG)nG, These findings suggest that the (CAG)nC configuration is related to repeat instability of the MJD gene.
  • M Hirano; Y Tamaru; H Ito; S Matsumoto; T Imai; S Ueno
    ANNALS OF NEUROLOGY 40 5 796 - 798 1996年11月 
    We present a new Japanese family with hereditary progressive dystonia with marked diurnal fluctuation/doparesponsive dystonia. The affected daughter and her asymptomatic father are heterozygous for a novel missense mutation that replaces His by Pro at codon 144 in the GTP cyclohydrolase I gene. Quantitative reverse transcription-polymerase chain reaction revealed a higher ratio of mutant/normal mRNA encoding GTP cyclohydrolase I in the patient. These results demonstrate the importance of mutant mRNA levels for phenotypic variability among cases with the same mutation.
  • Y Nagai; S Ueno; Y Saeki; F Soga; M Hirano; T Yanagihara
    NEUROLOGY 46 3 791 - 795 1996年03月 
    We investigated the dopamine receptor (DAR) mRNA expression in peripheral blood lymphocytes from 45 patients with Parkinson's disease (PD) and 21 age-matched controls using the quantitative reverse transcription and polymerase chain reaction method. beta-actin mRNA was used as an internal control to evaluate the relative expression level of the DAR mRNA. There was a statistically significant decrease of the D3 dopamine receptor (D3R) mRNA expression in PD patients compared with that in controls. There was no change in expression of the D5 dopamine receptor mRNA in PD patients. A further binding study showed reduction of the D3R binding sites in PD lymphocytes. The decrease of the D3R mRNA expression correlated with the degree of clinical severity in PD patients.
  • Y. Nagai; M. Hirano; T. Mori; Y. Takakura; S. Tamai; S. Ueno
    Neurology 46 2 571 - 574 1996年 
    We present the first case of triplets with cerebrotendinous xanthomatosis (CTX). A C-to-T base change identified in the genomic DNA and cDNA encoding the sterol 27-hydroxylase led to replacement of arginine by tryptophan at position 441 (Arg441Trp) in the triplets. The triplets were homozygous and their mother was heterozygous for this mutant gene. The triplets exhibited an identical phenotypic expression, which was different from that of a sporadic CTX case with the same mutation.
  • M. Hirano; K. Kuroda; M. Kunimoto; K. Tanohata; K. Inoue
    Clinical Neurology 35 1 80 - 82 1995年 
    We report a case of carpal tunnel syndrome (CTS) caused by a ganglion cyst which was diagnosed by magnetic resonance (MR) imaging of the left wrist. MR images depicted a 10-mm ganglion cyst which pressed the median nerve toward the ulnar side. The ganglion cyst was punctured under direct endoscopic visualization in the carpal canal, subsequently the clinical and the electrophysiologic findings of CTS improved. The median nerve was delineated in its proper position. MR imaging of the wrist, a noninvasive means to observe median nerve, is useful for the diagnosis and the follow-up study of CTS.
  • Makito Hirano; Yoshiko Tamaru; Yoshitaka Nagai; Hidefumi Ito; Terukuni Imai; Satoshi Ueno
    Biochemical and Biophysical Research Communications 213 2 645 - 651 1995年 
    We report a novel mutation at a splice site in the GTP cyclohydrolase I gene in a Japanese family with hereditary progressive dystonia with marked diurnal fluctuation (HPD)/dopa responsive dystonia (DRD). Reverse transcriptase-initiated PCR (RT-PCR) of lymphocyte mRNA showed both normal and small size fragments in the HPD patient and his asymptomatic mother. Sequence analysis revealed that skip splicing of exon 1 to exon 3 occurred in the small fragment. The patient and his mother were heterozygous for G→C substitution at conserved consensus sequence GT at 5′ end of the intron 2. Quantitative RT-PCR showed that the expression of normal GTP cyclohydrolase I mRNA decreased in their lymphocytes, while the HPD patient had more expression of mutant GTP cyclohydrolase I mRNA than his asymptomatic mother. © 1995 by Academic Press, Inc.
  • M. Hirano; J. Fujii; Y. Nagai; M. Sonobe; K. Okamoto; H. Araki; N. Taniguchi; S. Ueno
    Biochemical and Biophysical Research Communications 204 2 572 - 577 1994年10月 
    We have identified a new mutant Cu/Zn superoxide dismutase (SOD1) deduced from the nucleotide sequences of peripheral blood lymphocyte mRNA from Japanese patients with familial amyotrophic lateral sclerosis (FALS). Sequence analysis of reverse transcriptase-initiated PCR amplified mRNA revealed a heterozygosity indicative of one normal allele and one variant allele with a T→A transversion. This base change led to replacement of valine by glutamic acid at position 7 of 153-residue SOD1 molecule, and produced a new restriction site for Alu I in the exon I. Restriction fragment length polymorphism analysis confirmed the linkage of this mutation with this type of FALS. Both enzymatic activity and protein of the SOD1 were reduced in red blood cells from the patient.


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    WCN2019 2019年10月 口頭発表(一般)
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    第57回日本神経学会学術大会 2016年05月 ポスター発表
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    西田美紀; 平野愛; 西山未起; 穴見梓; 佐竹夏希; 竹下明美; 宮嶋沙織; 脇野昌司; 磯野千春; 上野周一; 阪本光; 平野牧人; 中村雄作
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    Hirano M; Nishida M; Nakamura Y; Saigoh K; Sakamoto H; Ueno S; Isono C; Kusunoki S
    26th international symposium on ALS/MND, Orlando 2015年12月 ポスター発表
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    第33回日本神経治療学会総会 2015年11月
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    上野 周一; 阪本 光; 平野 牧人; 中村 雄作
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    ANA 2015 (Chicago) 2015年09月 ポスター発表
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  • 2020年10月 第38回日本神経治療学会学術集会 優秀演題賞
    受賞者: 平野牧人
  • 2018年07月 近畿大学医学会 近畿大学医学会賞
    受賞者: 平野 牧人
  • 2017年07月 近畿大学医学会 近畿大学医学会賞
    受賞者: 平野 牧人
  • 2016年06月 近畿大学医学会 近畿大学医学会賞
    受賞者: 平野 牧人


  • SCA8関連筋萎縮性側索硬化症に対する治療薬の検証
    研究期間 : 2022年04月 -2023年03月 
    代表者 : 平野牧人; 竹原俊幸
  • ATXN8OS関連筋萎縮性側索硬化症における介在蛋白同定とiPS細胞モデル治療
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 平野 牧人
  • 筋萎縮性側索硬化症原因遺伝子ERBB4を介する発症機序解明と抗がん剤の効果検証
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 平野 牧人
  • ALS患者iPS細胞由来神経細胞に対するオートファジー促進薬や抗酸化薬による治療研究
    研究期間 : 2016年04月 -2017年03月 
    代表者 : 平野 牧人
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 楠 進; 西郷 和真; 平野 牧人; 宮本 勝一; 鍔田 武志
    糖脂質抗体陽性の免疫性神経疾患症例について、糖鎖への免疫反応を制御する分子の遺伝子解析を行ったところ、糖脂質抗体陽性のギラン・バレー症候群(GBS)の一部で特有の遺伝子変異がみられた。また各種糖脂質抗体陽性疾患の臨床特徴を調べたところ、ヒトの末梢神経のミエリンに局在するLM1関連抗原に対する抗体陽性の慢性ニューロパチー(CIDP)では脳神経障害が少なく運動失調が多いこと、ミエリンの抗原であるGal-Cに対する抗体陽性のGBSは脱髄型が多いことがわかった。IgMパラプロテイン血症を伴う末梢神経障害では、IgM M蛋白の反応特異性と臨床病型が関連することが明らかとなった。
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2013年 -2015年 
    代表者 : 平野 牧人
    1.患者iPS細胞の確立と神経への分化誘導すでに、予備実験で一部患者由来iPS細胞を確立していたが、本研究では、種々の異なる原因で生じる孤発性のALSや認知症も対象としており、できるだけ多くの患者のiPS細胞を樹立し、数種のiPS細胞で確認された知見を他の患者で確認する作業が必要である。このため、引き続き患者由来の線維芽細胞をiPS細胞に誘導し、新たに2例のiPS細胞を確立した。ALS患者から確立したiPS細胞を神経幹細胞さらに神経細胞へ分化誘導を行った。患者細胞では、神経突起伸展が阻害されていることが想定されていたが、実際には、明らかな伸展阻害は見られなかった。しかし、細胞内に凝集体が形成されていることが観察された。2.iPSから神経誘導におけるubiquilin2, p62の発現様式まず、基礎的情報収集のため行ったubiquilin2やp62発現に関して確認したが、iPS細胞においても、これら蛋白やそのmRNAは発現していることが証明された。また、凝集体はALS患者細胞でのみ観察された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2009年 -2011年 
    代表者 : 平野 牧人
    本研究の目的は、種々の神経変性疾患原因蛋白同士の相互作用、翻訳後修飾、細胞内局在を検討することである。翻訳後修飾はユビキチン化とリン酸化を対象とする。常染色体優性遺伝小脳失調症14型の原因遺伝子protein kinase Cγが常染色体劣性遺伝小脳失調症の原因遺伝子アプラタキシンのリン酸化を亢進し、核内輸送を妨げ、結果としてDNA修復蛋白でもあるアプラタキシンの核内欠乏を来たすことで、DNA損傷が蓄積し神経細胞の障害が生じることを証明した(Hum Mol Genet 2009 ; 18 : 3533)。また、X連鎖性優性遺伝の筋萎縮性側索硬化症(ALS)の原因蛋白として新たにubiquilin2を同定し、病理学的に、神経にこの蛋白およびそのほかのALS原因蛋白であるTDP43, FUS, Optineurinなどと共に家族性あるいは孤発性ALS患者の運動ニューロンにみられるユビキチン陽性封入体に凝集することを示した(Nature 2011 ; 477 : 211)。
  • 神経疾患の細胞モデルの構築
    研究期間 : 2006年 -2011年
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2008年 -2010年 
    代表者 : 上野 聡; 森 俊雄; 平野 牧人
    若年性劣性遺伝性パーキンソン病(ARJP)における異常遺伝子培養線維芽細胞ではDNA損傷の蓄積があり、正常Parkin遺伝子導入によって培養細胞生存率が向上することが判明した。Parkinがcyclin Eを基質とすることを証明し、患者細胞ではcyclin Eの細胞内含量の上昇によって、細胞周期の制御に変調をきたし、異常中心体を持つ細胞頻度が増加した。これから、患者細胞の発がんリスクも上昇する可能性を示唆した。治療戦略のひとつとして、アンチセンス法によってARJP細胞の生存率を向上することができた。さらに、遺伝性小脳失調症(SCA14)において、ProteinkinaseCγが常染色体遺伝子小脳失調症の原因遺伝子アプラタキシンのリン酸化を亢進させ、核内欠乏をきたすことを証明した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2007年 -2008年 
    代表者 : 平野 牧人
    本研究の目的は種々の神経変性疾患原因蛋白の核内輸送に関して、運動ニューロン病様Triple A症候群(AAAS)の原因である核膜孔蛋白アラジンに依存性であるかを検討し、本疾患で障害を受けやすい古典的な核局在シグナル(NLS)以外の輸送シグナル同定と輸送機序の解明である。本研究により小脳失調原因蛋白アプラタキシンのみAAASの輸送障害を受け、他の原因蛋白は障害を受けないことが判明した。また、核内輸送障害を受けないDNA修復蛋白であるXRCC1において、輸送障害を改善するために重要なのは、古典的NLS(239-266残基)の下流267-276残基であることを同定した。この部位を含む新規NLS(239-276残基)38アミノ酸配列をminimum essential sequence of stretched nuclear localization signal(mstNLS)と名付けた。mstNLSを融合すると、輸送障害を受けていた小脳失調原因蛋白アプラタキシンはAAAS患者細胞の核内に効率よく輸送された。さらに、mstNLSは酸化ストレス下の正常細胞においても、強力な核局在シグナルとなることが証明された。以上から本研究成果は、AAASの病態機序改善のみならず、核内輸送研究に貢献しうると考えられる。
  • 文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2003年 -2004年 
    代表者 : 平野 牧人
    眼球運動失行と低アルブミン血症を伴う早発型小脳失調症(EAOH)は本邦では最も多い常染色体劣性小脳失調症である。原因遺伝子アプラタキシンには既報告の1種に加え、新たに6種のスプライス変異体が存在することが本研究の予備実験により明らかされた。野生型を含む8種のmRNAは4種の蛋白をコードする。本研究の目的はこれらの野生型および変異型蛋白の発現解析とアプラタキシン機能解析である。大腸菌内で合成した変異型蛋白において、アプラタキシンの生理活性に関与すると考えられるHIT活性を測定したところ、全ての変異型蛋白で著しく低下していた。昨年度作製したモノクローナル抗体が反応する唯一の変異型蛋白および野生型蛋白の動物細胞内における半減期を、モノクローナル抗体によるパルス・チェイス法で測定したところ、変異型では野生型に比べ短縮していた。また、種々の変異型蛋白の野生型への結合能力をGST pull down法で検討した結果、全ての変異型は野生型に結合した。一方、病的異常蛋白(689insT変異)への結合能は低下しており、この変異型の野生型への結合能は病態生理学的に重要である可能性が考えられる。以上から、変異型蛋白自身は活性を持たないが、野生型に結合することで、その活性を調整している可能性が示唆された。また半減期が短いことも活性調整の目的には適していると考えられる。以上の成果は今後、アプラタキシンの機能解明、さらにはEAOHの治療法開発に貢献できると考えられる。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2002年 -2003年 
    代表者 : 上野 聡; 平野 牧人; 村田 顕也
    Humanin (HN)は、アルツハイマー病の原因となる遺伝子異常および変異アミロイドβ蛋白による神経細胞死を選択的に抑制するペプチドとして報告された(Nishino et al. Proc.Natl.Acad.Sci.USA 2001;98:6336)。本研究の目的は虚血や低酸素などの非特異的外的因子あるいは他疾患によってもたらされる細胞死がHNによって抑制される可能性、すなわちHNがより広い活性スペクトラムを有することを証明することである。ここでは神経細胞死のモデルとして一般的に用いられる無血清培養下でのラット褐色細胞種(PC12)細胞において、HNの細胞死抑制効果を検討した。その結果HNを培地中に添加することで、濃度依存性に細胞死が抑制され、それに伴い、アポトーシスのマーカーである核DNAの断片化も減少した。その機序としてアポトーシス過程で増加するcaspase 3活性をHNが抑制することを明らかにした。さらにこのHNの活性スペクトラムが神経系細胞に限らないことを証明するため、ヒトリンパ球を用いた研究を行った。PC12細胞同様に,無血清培養によるアポトーシスはHNによって有意に抑制された。この過程には細胞内ATP量増加を伴った。以上からHNは、ATP産生能障害を来たす疾患、例えばパーキンソン病やミトコンドリア脳筋症の治療薬としても期待される。そこで、ミトコンドリア脳筋症の代表的疾患であるMitochondrial Encephalopathy, Lactic acidosis, and Stroke-like episodes (MELAS)におけるHNの作用を検討した。ここでは容易に入手できるリンパ球を用いて,エネルギー消費を亢進させ,ミトコンドリア(Mt)DNAコピー数を増加させる環境下すなわち無血清培養を行った.予想通りMELASリンパ球はコントロールに比べて有意にATP量低下が認められるが,HN添加によって,細胞内ATP量増加,MtDNAコピー数増加の抑制,細胞死の減少が認められた.同様の効果は神経芽細胞種SK-N-MC細胞、骨格筋由来のTE671細胞でも証明され,MELASの臨床的特徴であるATP要求度の高い脳および筋での機能障害がHNにより抑制される可能性が考えられる.Mt異常を有する細胞ではATP産生能が低下し,フリーラジカルの産生が亢進する.アポトーシスは異常Mtを有する細胞を選択的に除去するという生体の防御機構であると同時に,細胞障害を誘発あるいは増幅して,さらなる組織障害を招来する.HNはこの悪循環を断つ、有力な治療薬候補と考えられる。以上から、HNはアルツハイマー病に対する効果のみならず、広い活性スペクトラムを有することが証明された。
  • 遺伝性小脳失調症の遺伝子治療
    研究期間 : 2002年
  • Gene Therapy for Hereditary Cerebellar Ataxia
    Cooperative Research
    研究期間 : 2002年


  • 2020年04月 - 2023年03月  非翻訳領域反復配列延長による筋萎縮性側索硬化症の病態解明と治療法開発 
    近畿大学学内研究助成金 研究種目:21 世紀研究開発奨励金【共同研究助成金】 課題番号:KD2001 研究内容:筋萎縮性側索硬化症(ALS)は、顔面、四肢、体幹、呼吸筋を支配する運動ニューロンの変性により、筋肉が徐々に萎縮する予後不良の神経難病である。現在、原因・根治療法は確立されていない。治療を考えるためにも、原因探索は重要である。私たちは、孤発性ALS患者を対象として、脊髄小脳萎縮症8型(SCA8)の原因遺伝子ATXN8OSの非翻訳領域反復配列延長を解析した結果、約3%に異常が認められることを発見し、報告した(Neurol Genet 2018;4:e252)。本研究では、病理学的に確定した ALS患者49例を含む250例を対象に、神経・筋疾患に関連する非翻訳領域の反復配列を解析し、新たなALS原因遺伝子の同定と、ALS患者iPS細胞由来の運動ニューロンモデルの構築、さらに異常RNAの発現・作用抑制に関する治療法開発を目指す。



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