Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP.
Dominantly inherited mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common cause of familial Parkinson's disease (PD) and have also been identified in individuals with sporadic PD. Although the exact cellular function of LRRK2 remains unknown, most PD-linked mutations appear to be toxic to cells in culture via mechanisms that depend on the kinase activity of LRRK2 or on the formation of cytoplasmic inclusions. Here we show that the E3 ubiquitin ligase CHIP physically associates with LRRK2 and regulates the cellular abundance of LRRK2. We further show that LRRK2 forms a complex with overexpressed and endogenous CHIP and Hsp90. Our data indicates that the destabilization of LRRK2 by CHIP is due to ubiquitination and proteasome-dependent degradation. Hsp90 can attenuate CHIP-mediated degradation and this can be blocked by the Hsp90 inhibitor geldanamycin. These findings provide important insight into the cellular regulation of LRRK2 stability and may lead to the development of therapeutics to treat PD based on controlling LRRK2 stability.
Ding
Xiaodong
X
Department of Neurology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Goldberg
Matthew S
MS
D000368:Aged; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000502:physiology*; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000737:chemistry; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D025801:Ubiquitin; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin