Investigation of pathophysiological mechanisms of synucleinopathy using cultured cellular model

• Project/Area Number: 21790831
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: KOBAYASHI Michiko Tohoku University, 大学院・医学系研究科, 非常勤講師 (40422109)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シヌクレイノパチー / シヌクレイン / 多系統萎縮症 / 異常タンパク凝集 / 細胞モデル / TPPP/p25 / GCI / オリゴデンドログリア / Sirtuin / αシヌクレイン / レビー小体 / TPPP / p25 / アグレソーム / 細胞死 / アポトーシス / SIRT2

Research Abstract

To clarify the molecular mechanisms of GCI formation and subsequent oligodendroglial degeneration, we ectopically expressed α-SYN and TPPP in HEK293T and oligodendroglial KG1C cell lines. Here we showed that TPPP specifically accelerated α-SYN oligomer formation and co-immunoprecipitation analysis revealed the specific interaction of TPPP and α-SYN. Moreover, phosphorylation of α-SYN at Ser-129 facilitated the TPPP-mediated α-SYN oligomerization. TPPP facilitated α-SYN-positive cytoplasmic perinuclear inclusions mimicking GCI in both cell lines ; however, apoptotic cell death was only observed in KG1C cells. This apoptotic cell death was partly rescued by sirtuin 2 inhibition.

Research Products

• [Journal Article] Role of TPPP/p25 on alpha-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy. (2010)
  • Author(s): Hasegawa T, Baba T, Kobayashi M, Konno M, Sugeno N, Kikuchi A, Itoyama Y, Takeda A
  • Journal Title: Neurochem Int 57 Pages: 857-66
  • Peer Reviewed
• [Journal Article] In vivo visualization of alpha-synuclein deposition by carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl ]-6-[2-(fluoro)ethoxy benzoxazole positron emission tomography in multiple system atrophy. (2010)
  • Author(s): Kikuchi A, Takeda A, Okamura N, Tashiro M, Hasegawa T, Furumoto S, Kobayashi M, Sugeno N, Baba T, Miki Y, Mori F, Wakabayashi K, Funaki Y, Iwata R, Takahashi S, Fukuda H, Arai H, Kudo Y, Yanai K, Itoyama Y.
  • Journal Title: Brain 133 Pages: 1772-1778
  • Peer Reviewed
• [Journal Article] Role of TPPP/p25 on alpha-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy. (2010)
  • Author(s): Hasegawa T, et al.
  • Journal Title: Neurochemisty International Volume: 57 Pages: 857-866
  • Peer Reviewed
• [Journal Article] Tyrosinase-expressing neuronal cell line as in vitro model of Parkinson's disease. (2010)
  • Author(s): Hasegawa T, et al.
  • Journal Title: Int J Mol Sci Volume: 11 Pages: 1082-1089
  • Peer Reviewed
• [Journal Article] In vivo visualization of alpha-synuclein deposition by carbon-11-labelled 2-[2-(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy]benzox azole positron emission tomography in multiple system atrophy (2010)
  • Author(s): Kikuchi A, et al
  • Journal Title: Brain Volume: 133 Pages: 1772-1778
  • Peer Reviewed
• [Journal Article] Tyrosinase-expressing neuronal cell line as in vivo model of Parkinson's disease (2010)
  • Author(s): Hasegawa T, et al.
  • Journal Title: Int J Mol Sci 11 Pages: 1082-9
  • Peer Reviewed
• [Journal Article] Functional imaging studies of hyposmia in Parkinson's disease (2010)
  • Author(s): Takeda A, et al.
  • Journal Title: J Neurol Sci 15 Pages: 36-9
  • Peer Reviewed
• [Journal Article] Parkin protects Mitochondrial Genome Integrity and supports Mitochondrial DNA Repair (2009)
  • Author(s): Rothfuss O, et al.
  • Journal Title: Hum Mol Genet 18 Pages: 3832-50
  • Peer Reviewed
• [Journal Article] Nuclear and neuritic distribution of serine-129 phosphorylated alpha-synuclein in transgenic mice (2009)
  • Author(s): Schell H, et al.
  • Journal Title: Neuroscience 160 Pages: 796-804
  • Peer Reviewed
• [Presentation] αシヌクレイン分泌・ライソゾーム移行を制御する細胞内膜動輸送系の探索 (2010)
  • Author(s): 長谷川隆文、馬場徹、小林理子、菅野直人、菊池昭夫、武田篤糸山泰人
  • Organizer: 日本パーキンソン病・運動障害疾患学会(Movement Disorder Society Japan ; MDSJ) 2010
  • Place of Presentation: 京都
  • Year and Date: 2010-10-07
• [Presentation] αシヌクレイン分泌ライソゾーム移行を制御する細胞内膜動輸送系の探索 (2010)
  • Author(s): 長谷川隆文, ほか
  • Organizer: MDSJ2010
  • Place of Presentation: 京都
  • Year and Date: 2010-10-07
• [Presentation] 細胞内へのα-synuclein取り込み機構の解析 (2010)
  • Author(s): 長谷川隆文、馬場徹、小林理子、菅野直人、菊池昭夫、武田篤、糸山泰人
  • Organizer: 第51回神経学会学術大
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] 細胞内へのα-synuclein取り込み機構の解析 (2010)
  • Author(s): 長谷川隆文, ほか
  • Organizer: 第51回神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2010-05-22
• [Presentation] GCI形成過程における Tubulin polymerization promoting protein の機能的役割 (2009)
  • Author(s): 小林理子
  • Organizer: 第50回日本神経学会総会(仙台)
  • Place of Presentation: 仙台市
  • Year and Date: 2009-05-21
• [Presentation] GCI形成過程におけるTubulin polymerization promoting proteinの機能的役割 (2009)
  • Author(s): 長谷川隆文、馬場徹、小林理子、菅野直人、菊池昭夫、武田篤、糸山泰人
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Remarks] 以下の東北大学神経内科教室のホームページにおいても、本研究結果の概要を提示している
  • URL: http://www.neurol.med.tohoku.ac.jp/