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.
Ko
Han Seok
HS
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Bailey
Rachel
R
Smith
Wanli W
WW
Liu
Zhaohui
Z
Shin
Joo-Ho
JH
Lee
Yun-Il
YI
Zhang
Yong-Jie
YJ
Jiang
Haibing
H
Ross
Christopher A
CA
Moore
Darren J
DJ
Patterson
Cam
C
Petrucelli
Leonard
L
Dawson
Ted M
TM
Dawson
Valina L
VL
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019281:Dimerization; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism / Q000628:therapy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000633:toxicity; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
D018841:HSP90 Heat-Shock Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases