Research on the molecular pathogenetic mechanism of tissue-specific toxicity mediated by ALS-linked mutant SOD1

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Aichi Medical University
• Principal Investigator: NIWA Jun-ichi Aichi Medical University, 医学部, 講師 (50378022)
• Co-Investigator(Renkei-kenkyūsha): SOBUE Gen 名古屋大学, 大学院・医学系研究科, 教授 (20148315) ; TANAKA Fumiaki 名古屋大学, 大学院・医学系研究科, 准教授 (30378012)
• Project Period (FY): 2007 – 2008
• Keywords: 筋萎縮性側索硬化症(ALS) / 神経変性 / 変異SOD1 / Dorfin / タンパク質凝集 / ユビキチン化 / ジスルフィド結合 / プロテオーム

Research Abstract

SOD1タンパク質は内部にジスルフィド(S-S)結合を形成しうるシステイン残基を4ヶ所(6, 57, 111, 146番アミノ酸)有しており、これらのうち57番と146番が酸化され相互にS-S結合を形成してSOD1分子を安定させている。我々は、6番と111番のシステイン残基の異常な酸化が変異SOD1特異的に脳幹・脊髄で生じてタンパク質凝集を促進し、高分子複合体を形成することで運動ニューロンに毒性を発揮して、筋萎縮性側索硬化症(ALS)を引き起こしていることを見出した。

Research Products

• [Journal Article] TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases (2009)
  • Author(s): Iguchi Y, Katsuno M, Niwa J, Yamada S, Sone J, Waza M, Adachi H, Tanaka F, Nagata K, Arimura N, Watanabe T, Kaibuchi K, Sobue G.
  • Journal Title: J Biol Chem (in press)
  • Peer Reviewed
• [Journal Article] Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis (2009)
  • Author(s): Sone J, Niwa J, Kawai K, Ishigaki S, Yamada S, Adachi H, Katsuno M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: J Neurosci Res (in press)
  • Peer Reviewed
• [Journal Article] Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1 (2007)
  • Author(s): Niwa J, Yamada S, Ishigaki S, Sone J, Takahashi M, Katsuno M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: J Biol Chem 282 Pages: 28087-28095
  • Peer Reviewed
• [Journal Article] Gene expressions specifically detected in motor neurons (dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to pathologic markers in sporadic amyotrophic lateral sclerosis (2007)
  • Author(s): Jiang YM, Yamamoto M, Tanaka F, Ishigaki S, Katsuno M, Adachi H, Niwa J, Doyu M, Yoshida M, Hashizume Y, Sobue G.
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 617-627
  • Peer Reviewed
• [Journal Article] Gene expression profiling toward understanding of ALS pathogenesis (2007)
  • Author(s): Tanaka F, Niwa J, Ishigaki S, Katsuno M, Waza M, Yamamoto M, Doyu M, Sobue G.
  • Journal Title: Ann N Y Acad Sci 1086 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity (2007)
  • Author(s): Ishigaki S, Niwa J, Yamada S, Takahashi M, Ito T, Sone J, Doyu M, Urano F, Sobue G.
  • Journal Title: Neurobiol Dis 25 Pages: 331-341
  • Peer Reviewed
• [Presentation] 孤発性ALS病態関連分子の探索と疾患モデルの開発 (2008)
  • Author(s): 田中章景, 和座雅浩, 丹羽淳一, 山本正彦, 祖父江元
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-17
• [Presentation] 変異SOD1と特異的に結合するタンパク質の探索同定 (2007)
  • Author(s): 丹羽淳一、山田新一、曽根淳、高橋美穂、道勇学、祖父江元
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-17