Investigation for developing a novel immunotherapy for a degenerative ataxia common in Japan.

• Project/Area Number: 19590981
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ISHIKAWA Kinya Tokyo Medical and Dental University, 医学部附属病院, 講師 (30313240)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 遺伝子 / 神経 / 遺伝 / 蛋白 / 脊髄小脳変性症 / イオンチャネル / 脳 / 細胞 / 神経疾患 / モノクローナル抗体 / 免疫治療 / 分子標的治療 / 脊随小脳変性症 / 神経難病 / 小脳 / 遺伝子治療

Research Abstract

脊髄小脳失調症6型(spinocerebellar ataxia type 6 ; SCA6)は、本邦に高頻度に存在する常染色体優性遺伝性脊髄小脳変性症で、α1A-カルシウムチャネル遺伝子内の3塩基(CAG)繰り返し配列が異常に伸長するために起きる疾患であり、このチャネル蛋白が神経細胞内で凝集・沈着することが病態に関連している。本研究では、SCA6の基本病態を明らかにし、それに基づく画期的な免疫療法を開発するための基礎研究を行った。その成果として、チャネル蛋白の凝集・沈着には、このチャネル蛋白のC末端部分が重要であることを初めて明らかにし、この部分を特異的に認識するモノクローナル抗体を得た。この成果をもとに、抗体療法を開発するという発展が期待された。

Research Products

• [Journal Article] Spinocerebellar ataxia type 6 knock-in mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels (2008)
  • Author(s): Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW and Zoghbi HY
  • Journal Title: Proc Natl Acad Sci USA 105(33) Pages: 11987-92
• [Journal Article] Cell-type-specific alternative splicing in spinocerebellar ataxia type 6 (2008)
  • Author(s): Tsunemi T, Ishikawa K, Jin H, Mizusawa H
  • Journal Title: Neurosci Lett 30
• [Journal Article] Direct and accurate measurement of CAG repeat configuration in the ataxin-1(ATXN-1)gene by "dual-fluorescence labeled PCR-restriction fragment length analysis" (2008)
  • Author(s): Lin J. X, Ishikawa K(Corresponding author), Sakamoto M, Tsunemi T, Ishiguro T, Amino T, Toru S, Kondo I, Mizusawa H
  • Journal Title: J Hum Genet 53 Pages: 287-295
  • NAID: 10021248419
• [Journal Article] Analyses of copy number and mRNA expression level of the [alpha]-synuclein gene in multiple system atrophy (2008)
  • Author(s): Honglian Jin, Ishikawa K(Corresponding author), Tsunemi T, Ishiguro T, Mizusawa H
  • Journal Title: J Med Dent Sci 55 Pages: 145-153
• [Journal Article] Cell-type-specific alternative splicing in spino-cerebellar ataxia type 6. (2008)
  • Author(s): Tsunemi T, Ishikawa K, Jin H, Mizusawa H.
  • Journal Title: Neurosci Lett. 447(1) Pages: 78-81
  • Peer Reviewed
• [Journal Article] Spinocerebellar ataxia type 6 knockin mice devel op aprogressive neuronal dysfunction with age-dependentaccumulation of mutant Ca_v2. 1 channels. (2008)
  • Author(s): Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY.
  • Journal Title: Proc Natl Acad Sci USA 105(33) Pages: 11987-11992
  • Peer Reviewed
• [Journal Article] Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia (2007)
  • Author(s): Amino T, Ishikawa K(Corresponding author), Toru S, Ishiguro T, Sato N, Tsunemi T, Murata M, Kobayashi K, Inazawa J, Toda T, Mizusawa H
  • Journal Title: J Hum Genet 52 Pages: 643-649
  • NAID: 10019812756
• [Journal Article] Bax-inhibiting peptide protects cells from polyglutamine toxicity caused by Ku70 acetylation (2007)
  • Author(s): Li Y, Yokota T, Gama V, Yoshida T, Gomez JA, Ishikawa K, Sasaguri H, Cohen HY, Sinclair DA, Mizusawa H, Matsuyama S
  • Journal Title: Cell Death Differ 14(12) Pages: 2058-67
• [Presentation] Spinocerebellar ataxia type 6(SCA6)is associated withsmall α1A-calcium channel protein aggregates containing expanded polyglutamine in the cytoplasm and the nucleusof human Purkinje cells (2008)
  • Author(s): Ishikawa K, Ishiguro T, Takahashi M, Amino T, Mizusawa H
  • Organizer: 第58回米国人類遺伝学会年次大会
  • Place of Presentation: 米国フィラデルフィア市
  • Year and Date: 2008-11-13
• [Presentation] Spinocerebellar ataxia type 6 (SCA6) is associ ated withsmall alA-calcium channel protein aggregates containingexpanded polyglutamine in the cytoplasm and the nucleusof human Purkinje cells. (2008)
  • Author(s): Ishikawa K, Ishiguro T, Takahashi M, Amino T, Mizusawa H.
  • Organizer: 第58回 米国人類遺伝学会年次大会
  • Place of Presentation: 米国フィラデルフィア市
  • Year and Date: 2008-11-13
• [Book] Chromosome 16q22.1-linked autosomal dominant cerebellar ataxia and spinocerebellar ataxia type 4, the clinically distinct ataxias linked to the same locus. In, "Research advances in spinocerebellar degeneration and spastic paraplegia"
  • Author(s): Ishikawa K, Flanigan K, Mizusawa H
  • Publisher: Nishizawa M & Takiyama Y, Editors Research SignPost, Kerala, India