Abstract
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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and affects 1–2% of the population over 60 years old
DNA sequencing revealed that the interactor of the ARM domain corresponded to the C-terminal portion of heat shock protein 90 (Hsp90) from amino acid 248 to amino acid 704 and the interactor of the ROC domain corresponded to the charged domain of the E3 ubiquitin ligase CHIP from amino acid 150 to amino acid 200
Co-transfection of HEK293 cells followed by immunoprecipitation and western blotting showed that the ROC domain of leucine-rich repeat kinase 2 gene (LRRK2) robustly co-immunoprecipated with CHIP150–200 (Figure 1A, right lane), and the ARM domain of LRRK2 co-immunoprecipitated with Hsp90248–stop (Figure 1B, right lane)
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and affects 1–2% of the population over 60 years old. Epidemiological studies have failed to definitively identify a single cause for PD, age is the greatest risk factor and many studies have implicated cumulative oxidative stress, mitochondrial dysfunction, protein aggregation and neuroinflammation in PD pathogenesis or progression [1,2,3,4]. PD is generally sporadic, many families are known to have a Mendelian pattern of inherited parkinsonism. The recent identification of several genes with mutations linked to familial forms of PD has provided unprecedented opportunities to discover potential pathogenic mechanisms and to rationally develop more effective therapies [5]
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