Molecular pathogenesis of Parkinson's disease

2009 Fiscal Year Final Research Report

• Project/Area Number: 17025009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: IWATSUBO Takeshi The University of Tokyo, 大学院・医学系研究科, 教授 (50223409)
• Project Period (FY): 2005 – 2009
• Keywords: パーキンソン病 / αシヌクレイン / LRRK2 / 神経変性

Research Abstract

Using transgenic C. elegans that pan-neuronally overexpress human alpha-synuclein in neurons, we searched for genes that modify the neurotoxicity of alpha-synuclein, and identified endocytosis-related genes as modifiers. These results suggest that impairment in endocytotic function is involved in the mechanism of neurodegeneration of PD. We also found that GTP binding is essential to the kinase activity of LRRK2, a responsible gene product of PARK8. We also found that autophosphorylation of Thr1410 and Thr1967 of LRRK2 is important for the regulation of its kinase activity.

Research Products

• [Journal Article] Identification of the autophosphorylation sites of LRRK2 linked to familial Parkinson's disease. (2009)
  • Author(s): Kamikawaji, S., Ito, G., Iwatsubo, T.
  • Journal Title: Biochemistry 48 Pages: 10963-10975
  • Peer Reviewed
• [Journal Article] A large-scale RNA interference screen identifies endocytic pathway genes as modifiers of α-synuclein toxicity in transgenic Caenorhabditis elegans. (2008)
  • Author(s): Kuwahara, T, Koyama A., Koyama, S., Yoshina, S., Ren, C. -H., Kato, T., Mitani, S., Iwatsubo, T.
  • Journal Title: Human Molecular Genetics 17 17 Pages: 2997-3009
  • Peer Reviewed
• [Journal Article] GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease. (2007)
  • Author(s): Ito, G., Okai, T., Fujino, G., Takeda, K., Ichijo, H., Katada, T., Iwatsubo, T.
  • Journal Title: Biochemistry 46 Pages: 1380-1388
  • Peer Reviewed
• [Journal Article] Familial Parkinson mutantα-synuclein causes dopamine neuron dysfunction in transgenic C. elegans. (2006)
  • Author(s): Kuwahara, T., Koyama, A., Gengyo-Ando, K., Masuda, M., Kowa, H., Tsunoda, M., Mitani, S., Iwatsubo, T.
  • Journal Title: J. Biol. Chem. 281 Pages: 334-340
  • Peer Reviewed