A basic research for identifying fundamental therapy for SCA6 and SCA31

• Project/Area Number: 21249054
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIZUSAWA Hidehiro 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (30144091)
• Co-Investigator(Kenkyū-buntansha): ISHIKAWA Kinya 東京医科歯科大学, 医学部附属病院, 講師 (30313240) ; WATASE Kei 東京医科歯科大学, 脳統合機能研究センター, 准教授 (30376800)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥46,800,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥10,800,000); Fiscal Year 2011: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2010: ¥11,440,000 (Direct Cost: ¥8,800,000、Indirect Cost: ¥2,640,000); Fiscal Year 2009: ¥26,520,000 (Direct Cost: ¥20,400,000、Indirect Cost: ¥6,120,000)
• Keywords: 遺伝子 / 蛋白質 / 応用動物 / 内科 / 脳神経疾患 / 脊髄小脳失調症 / Caチャンネル / 培養細胞 / 封入体

Research Abstract

We performed basic research for three years(FY2009-2011) and achieved three key developments toward discovering drugs that that may be able to stop primary degenerative processes in spinocerebellar ataxia type 6(SCA6) and 31(SCA31). First, we found that the carboxyl-terminal fragment of the 1A-calcium channel is toxic when expressed in the cytoplasm. Second, we succeeded in developing a cellular model that could efficiently monitor the splicing patterns of the 1A-calcium channel gene. This model could be useful for future drug screens. Third, we found a penta-nucleotide sequence that is necessary for the development of SCA31. These achievements are crucial for the future establishment of treatments of SCA6 and SCA31.

Research Products

• [Journal Article] Reduced brain-derived neurotrophic factor(BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6(SCA6) cerebellum. (2012)
  • Author(s): Takahashi M, Ishikawa K, Sato N, Obayashi M, Niimi Y, Ishiguro T, Yamada M, Toyoshima Y, Takahashi H, Kato T, Takao M, Murayama M, Mori O, Eishi Y, Mizusawa H
  • Journal Title: Neuropathology Volume: (in press)
• [Journal Article] Prevalence of inositol 1, 4, 5-triphosphate receptor type 1 gene(ITPR1) deletion, the mutation for spinocerebellar ataxia type 15(SCA15), in Japan screened by gene dosage (2012)
  • Author(s): Obayashi M, Ishikawa K, Izumi Y, Takahashi M, Niimi Y, Sato N, Onodera O, Kaji R, Nishizawa M, Mizusawa H
  • Journal Title: J Hum Genet Volume: 57(3) Pages: 202-206
• [Journal Article] Reduced brain-derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF-immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum (2012)
  • Author(s): Takahashi M, Ishikawa K, Sato N, Obayashi M, Niimi Y, Ishiguro T, Yamada M, Toyoshima Y, Takahashi H, Kato T, Takao M, Murayama M, Mori O, Eishi Y, Mizusawa H
  • Journal Title: Neuropathology Volume: (in press) Issue: 6 Pages: 593-603
  • DOI: 10.1111/j.1440-1789.2012.01302.x
  • Peer Reviewed
• [Journal Article] Prevalence of inositol 1,4,5-triphosphate receptor type 1 gene (ITPR1) deletion, the mutation for spinocerebellar ataxia type 15 (SCA15), in Japan screened by gene dosage (2012)
  • Author(s): Obayashi M, Ishikawa K, Izumi Y, Takahashi M, Niimi Y, Sato N, Onodera O, Kaji R, Nishizawa M, Mizusawa H
  • Journal Title: J Hum Genet Volume: 57(3) Issue: 3 Pages: 202-206
  • DOI: 10.1038/jhg.2012.5
  • Peer Reviewed
• [Journal Article] Pentanucleotide repeats at the spinocerebellar ataxia type 32(SCA31) locus in Caucasians (2011)
  • Author(s): Ishikawa K, Durr A, Klopstock T, M ller S, De Toffol B, Vighetto A, Marelli C, Wichmann HE, Illig T, Niimi Y, Sato N, Amino T, Stevanin G, Brice A, Mizusawa H
  • Journal Title: Neurology Volume: 77(20) Pages: 1853-1855
• [Journal Article] Pentanucleotide repeats at the spinocerebellar ataxia type 32 (SCA31) locus in Caucasians (2011)
  • Author(s): Ishikawa K, Durr A, Klopstock T, Muller S, De Toffol B, Vighetto A, Marelli C, Wichmann HE, Illig T, Niimi Y, Sato N, Amino T, Stevanin G, Brice A, Mizusawa H
  • Journal Title: Neurology Volume: 77(20) Pages: 1853-1855
  • Peer Reviewed
• [Journal Article] Suppression of the novel ER proteinMaxer by mutant ataxin-1 in Bergmanglia contributes tonon-cell-autonomous toxicity (2010)
  • Author(s): Shiwaku, H., Yoshimura, N., Tamura, T., Sone, M., Ogishima, S., Watase, K., Tagawa, K. and Okazawa H.
  • Journal Title: EMBO J Volume: 29(14) Pages: 2446-2460
• [Journal Article] The chromosome 16q-linked autosomal dominant cerebellar ataxia(16q-ADCA*): A newly identified degenerative ataxia in Japan showing peculiar morphological changes of the Purkinje cell (2010)
  • Author(s): Ishikawa K, Mizusawa H
  • Journal Title: Neuropathology Volume: 30(5) Pages: 490-494
• [Journal Article] The carboxy-terminal fragment of alpha1A calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells (2010)
  • Author(s): Ishiguro T, Ishikawa K, Takahashi M, Obayashi M, Amino T, Sato N, Sakamoto M, Fujigasaki H, Tsuruta F, Dolmetsch R, Arai T, Sasaki H, Nagashima K, Kato T, Yamada M, Takahashi H, Hashizume Y, Mizusawa H
  • Journal Title: Acta Neuropathol Volume: 119(4) Pages: 447-464
• [Journal Article] カルシウムチャネルのCAGリピート病-SCA6ノックインマウスの解析による病態解明 (2010)
  • Author(s): 渡瀬啓、海野敏紀
  • Journal Title: 実験医学 Volume: 28 Pages: 118-123
• [Journal Article] The carboxy-terminal fragment of alphalA calcium channelpreferentially aggregates in the cytoplasm of human spino-cerebellar ataxia type 6 Purkinje cells. (2010)
  • Author(s): Ishiguro T, Ishikawa K, Takahashi M, Obayashi M, Amino T, Sato N, Sakamoto M, Fujigasaki H, Tsuruta F, Dolmetsch R, Arai T, Sasaki H, Nagashima K, Kato T, Yamada M, Takahashi H, Hashizume Y, Mizusawa H.
  • Journal Title: Acta Neuropathologica Volume: 119(4) Pages: 447-464
  • Peer Reviewed
• [Journal Article] The chromosome 16q-linked autosomal dominant cerebellarataxia (16q-ADCA*) : A newly identified degenerative ataxiain Japan showing peculiar morphological changes of the Purkinje cell. (2010)
  • Author(s): Ishikawa K, Mizusawa H
  • Journal Title: Neuropathology
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 31 is associated with "inserted" penta-nucleotide repeats containing(TGGAA) n (2009)
  • Author(s): Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, Takahashi M, Matsuura T, Flanigan KM, Iwasaki S, Ishino F, Saito Y, Murayama S, Yoshida M, Hashizume Y, Takahashi Y, Tsuji S, Shimizu N, Toda T, Ishikawa K, Mizusawa H
  • Journal Title: Am J Hum Genet Volume: 85(5) Pages: 544-557
• [Journal Article] The carboxy-terminal fragment of alpha1A calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells. (2009)
  • Author(s): Ishiguro T, Ishikawa K, Takahashi M, Obayashi M, Amino T, Sato N, Sakamoto M, Fujigasaki H, Tsuruta F, Dolmetsch R, Arai T, Sasaki H, Nagashima K, Kato T, Yamada M, Takahashi H, Hashizume Y, Mizusawa H.
  • Journal Title: Acta Neuropathol Volume: Dec 31(Epub ahead of print)
  • Peer Reviewed
• [Presentation] A novel mouse model of spinocerebellar ataxia type 6 develops distinct Purkinje cell degeneration (2011)
  • Author(s): Unno T, Mizusawa H, Watase K
  • Organizer: 12^<th> International Congress of Human Genetics/61^<st> Annunal Meeting of the American Society of Human Genetics.
  • Place of Presentation: Montreal, Quebec, Canada
  • Year and Date: 2011-10-12
• [Presentation] ノックインマウスモデルを用いた脊髄小脳変性症の病態解明 (2011)
  • Author(s): 渡瀬啓
  • Organizer: 第28回東京医科歯科大学大学院医歯学総合研究科大学院セミナー
  • Place of Presentation: 東京
  • Year and Date: 2011-06-27
• [Presentation] 細胞モデルを用いた脊髄小脳失調症31型(SCA31)の病態探索 (2011)
  • Author(s): 新美祐介,佐藤望,網野猛志,高橋真,大林正人,石黒太郎,石川欽也,水澤英洋
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] SCA6遺伝子エクソン47のスプライスパターンを再現する細胞系の確立 (2011)
  • Author(s): 相川知徳、水澤英洋、渡瀬啓
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Presentation] 脊髄小脳変性症6型の治療法開発に向けたマウスモデルの開発 (2010)
  • Author(s): 渡瀬啓
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
  • Year and Date: 2010-09-18
• [Presentation] The carboxy-terminal fragment of alA-calcium channel behavior underlies SCA6 neurodegeneration. (2010)
  • Author(s): T.Ishiguro, K.Ishikawa, (途中12名), H.Mizusawa.
  • Organizer: 17^<th> International Congress of Neuropathology
  • Place of Presentation: ザルツブルク市、オーストリア
  • Year and Date: 2010-09-14
• [Presentation] SCA31 : Anew SCA identified in Japan showing peculiar pathology of Purkinje cells. (2010)
  • Author(s): K.Ishikawa, (途中7名), H.Mizusawa.
  • Organizer: 17^<th> International Congress of Neuropathology
  • Place of Presentation: ザルツブルク市、オーストリア
  • Year and Date: 2010-09-13
• [Presentation] SCA6原因の同定から治療法の開発へ (2010)
  • Author(s): 渡瀬啓,石川欽也,水澤英洋
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] シンポジウム16.「Neurodegenerative diseases and RNA.」SCA31 (2010)
  • Author(s): 石川欽也、網野猛志、佐藤望,新美祐介,融衆太,水澤英洋
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] シンポジウム:神経難病の克服 -単一遺伝子病からのアプローチーSCA6-原因の同定から治療法の開発へ- (2010)
  • Author(s): 渡瀬啓, 石川欽也, 水澤英洋
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] シンポジウム「神経変性疾患とRNA」演題:SCA31 (2010)
  • Author(s): 至川欽也、網野猛志、佐藤望、新美祐介、融衆太、水澤英洋
  • Organizer: 第51回 日本神経学会総会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] わが国によく見られる脊髄小脳失調症31型の臨床と分子病理 (2009)
  • Author(s): 水澤英洋
  • Organizer: 第39回日本臨床生理学会学術大会
  • Place of Presentation: 北九州
  • Year and Date: 2009-11-18
• [Presentation] シンポジウム9-1ポリグルタミン病への分子生物学的アプローチ.「脊髄小脳変性症への分子生物学的アプローチ」 (2009)
  • Author(s): 石川欽也,石黒太郎,高橋真,佐藤望,網野猛志,新美祐介,水澤英洋
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] SCA6ノックインマウス表現型の経時的検討 (2009)
  • Author(s): 渡瀬啓, Barrett CF,宮崎太輔、海野敏紀、石川欽也、笠井沙由美、渡辺雅彦、水澤英洋、Tsien RW, Zoghbi HY
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-20
• [Presentation] 50周年記念標本提示「日本が世界に発信したあの疾患」本邦で同定された新しい脊髄小脳変性症16q-ADCA-その特異的Purkinje細胞変性- (2009)
  • Author(s): 石川欽也,水澤英洋
  • Organizer: 第50回日本神経病理学会総会学術研究会
  • Place of Presentation: 高松
• [Presentation] 脊髄小脳変性症の分子病態
  • Author(s): 石川欽也、水澤英洋
  • Organizer: 第28回日本医学会総会
  • Place of Presentation: 震災のため抄録発表のみ
• [Book] 脊髄小脳変性症6型(SCA6)モデルマウス脳・神経疾患-疾患モデルの作製と利用 (2011)
  • Author(s): 渡瀬啓、水澤英洋
  • Publisher: エル・アイ・シー
• [Book] 脊髄小脳失調症31型(SCA31) (2011)
  • Author(s): 石川欽也,佐藤望,網野猛志,新美祐介,融衆太,水澤英洋
  • Publisher: Annual Review神経
• [Book] 脳・神経疾患-疾患モデルの作製と利用 (2011)
  • Author(s): 渡瀬啓、水澤英洋
  • Total Pages: 8
  • Publisher: エル・アイ・シー
• [Book] 遺伝性脊髄小脳変性症.雑誌「内科」特集「内科疾患の診断基準病型分類・重症度」 (2010)
  • Author(s): 石川欽也、水澤英洋
  • Publisher: 南江堂、東京
• [Book] 不随意運動.雑誌「内科」特集「内科疾患の診断基準病型分類・重症度」 (2010)
  • Author(s): 石川欽也、水澤英洋
  • Total Pages: 1398
  • Publisher: 南江堂、東京
• [Book] 脊髄小脳変性症の分類と治療 (2010)
  • Author(s): 石川欽也、水澤英洋
  • Publisher: 日本評論社,東京
• [Book] 脊髄小脳変性症 (2009)
  • Author(s): 石川欽也
  • Publisher: 学研,東京
• [Book] 多系統萎縮症 (2009)
  • Author(s): 石川欽也
  • Publisher: 学研,東京
• [Book] パーキンソン病のようにみえる脊髄小脳変性症.In:水野美邦編.パーキンソン病診療Q&A (2009)
  • Author(s): 水澤英洋
  • Total Pages: 361
  • Publisher: 中外医学社