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

http://www.ncbi.nlm.nih.gov/pubmed/19196961

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 RIS Download

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

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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
  • Agency: NINDS NIH HHS, Id: P50 NS038377
  • Agency: NINDS NIH HHS, Id: R01 NS048206
  • Agency: NINDS NIH HHS, Id: R21 NS054207

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