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CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity.

Mutation in leucine-rich repeat kinase-2 (LRRK2) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.

Pubmed ID: 19196961

Authors

  • Ko HS
  • Bailey R
  • Smith WW
  • Liu Z
  • Shin JH
  • Lee YI
  • Zhang YJ
  • Jiang H
  • Ross CA
  • Moore DJ
  • Patterson C
  • Petrucelli L
  • Dawson TM
  • Dawson VL

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 24, 2009

Associated Grants

  • Agency: NIA NIH HHS, Id: AG017216
  • Agency: NINDS NIH HHS, Id: NS04826
  • Agency: NINDS NIH HHS, Id: NS38377
  • Agency: NINDS NIH HHS, Id: NS54207

Mesh Terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Dimerization
  • HSP90 Heat-Shock Proteins
  • Humans
  • Hydrolysis
  • Immunoprecipitation
  • Mice
  • Parkinson Disease
  • Protein-Serine-Threonine Kinases
  • Substrate Specificity
  • Ubiquitin-Protein Ligases
  • Ubiquitination