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Regulation of LRRK2 stability by the E3 ubiquitin ligase CHIP

Department of Neurology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(6):e5949. DOI: 10.1371/journal.pone.0005949
Source: PubMed

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.

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    • "Hsp90 can also inhibit αsynuclein aggregation by interaction with soluble oligomers (Daturpalli et al. 2013; Falsone et al. 2009). In Parkinson's models, CHIP and Hsp90 both modulate the stability of leucine-rich repeat kinase 2 (LRRK2), a protein in which mutations increase the risk for developing Parkinson's disease (Ding and Goldberg 2009; Hurtado-Lorenzo and Anand 2008; Ko et al. 2009; Rudenko et al. 2012; Wang et al. 2008). Furthermore, the mitochondrial Hsp90 protein, tumor necrosis factor receptor-associated protein 1 (TRAP1), is known to mitigate α-synuclein toxicity (Butler et al. 2012). "
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    • "Indeed, a complex formed between LRRK2, CHIP, and Hsp90 appears to regulate cell LRRK2 levels. Hsp90 overexpression reduces CHIP-mediated LRRK2 degradation and geldanamycin, an Hsp90 inhibitor, increases CHIP-mediated LRRK2 degradation (Ding and Goldberg, 2009; Ko et al., 2009). The effect of whether or not LRRK2 mutations interfere with its Hsp90/CHIP interactions, though, is unknown. "
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