regulation of lrrk2 stability by the e3 ubiquitin ligase chip体内基因lrrk2的监管e3泛素连接酶稳定的芯片.pdfVIP

Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP 1 1,2 Xiaodong Ding , Matthew S. Goldberg * 1 Department of Neurology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America, 2 Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America 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. Citation: Ding X, Goldberg MS (2009) Regulation of LRRK2 Stability by the E3 Ubiquitin Ligase CHIP. PLoS ONE 4(6): e5949. doi:10.1371/journal.pone.0005949 Editor: Mark R. Cookson, National Institutes of Health, United States of America Received December 26, 2008; Accepted April 27, 2009; Published June 17, 2009 Copyright: 2009 Ding, Goldberg. This is an open-access ar