Elucidation of cell death mechanism by mutant LRRK2, the causative molecule of familial Parkinson's disease

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790848
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Kitasato University
• Principal Investigator: OHTA Etsuro Kitasato University, 医療衛生学部, 助教 (60508042)
• Project Period (FY): 2009 – 2010
• Keywords: パーキンソン病 / LRRK2 / 細胞内分解 / 蛋白質安定性 / アポトーシス抑制能

Research Abstract

Mutant LRRK2 is the causal molecule for autosomal dominant familial Parkinson's disease. In the present study, we demonstrated that the protective effect of I2020T LRRK2 against hydrogen peroxide-induced apoptosis was impaired in comparison with the wild-type (WT) molecule. Also, Pulse-chase experiments proved that the I2020T LRRK2 molecule has a higher degradation rate than WT or G2019S LRRK2. Upon addition of proteasome and lysosome inhibitors, the protein level of I2020T mutant LRRK2 reached that of WT LRRK2, and simultaneously the mutant LRRK2 exhibited an elevated protective effect against apoptosis. We further confirmed that a decrease in the intracellular protein level of WT LRRK2 by knocking down resulted in a reduction of protectivity against apoptosis.

Research Products

• [Journal Article] Prevention of intracellular degradation of I2020T mutant LRRK2 restores its protectivity against apoptosis. (2010)
  • Author(s): Ohta E, Kubo M, Obata F.
  • Journal Title: Biochemical and Blophysical Research Communications 391(1) Pages: 242-247
  • Peer Reviewed
• [Journal Article] I^<2020>T leucine-rich repeat kinase 2, the causative mutant molecule of familial Parkinson's disease, has a higher intracellular degradation rate than the wild-type molecule. (2009)
  • Author(s): Ohta E, Katayama Y, Kawakami F, Yamamoto M, Tajima K, Maekawa T, Iida N, Hattori S, Obata F
  • Journal Title: Bzochemical and Biophysical Research Communications 390(3) Pages: 710-715
  • Peer Reviewed
• [Presentation] LRRK2の細胞内半減期がアポトーシス抑制能に及ぼす影響-ノックダウンによる解析- (2010)
  • Author(s): 太田悦朗、川上文貴、飯田直幸、山元茉莉、前川達則、服部成介、小幡文弥
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 日神戸国際展示場(兵庫県)
  • Year and Date: 2010-12-08
• [Presentation] LRRK2の細胞内半減期およびLRRK2ノックダウン下における細胞生存率の解析 (2010)
  • Author(s): 太田悦朗、川上文貴、飯田直幸、山元茉莉、前川達則、服部成介、小幡文弥
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京国際フォーラム(東京都)
  • Year and Date: 2010-05-20
• [Presentation] Mutant (I^<2020>T) LRRK2 has a higher susceptibility to ploteolysis and impaired protectivity against apoptosis. (2009)
  • Author(s): Ohta E, Katayama Y, Tajima K, Maekawa T, Yamamoto M, Obata F.
  • Organizer: XVIII WFN World Congress on Parkinson's Disease and Related Disorders
  • Place of Presentation: Maiami Beach convention center (Florida, USA)
  • Year and Date: 2009-12-16
• [Presentation] LRRK2安定発現SH-SY5Y細胞株の樹立およびアポトーシス抑制能の解析 (2009)
  • Author(s): 太田悦朗、山元茉莉、前川達則、小幡文弥
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台国際センター(宮城県)
  • Year and Date: 2009-05-20