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.

[1]  David W. Miller,et al.  Kinase activity is required for the toxic effects of mutant LRRK2/dardarin , 2006, Neurobiology of Disease.

[2]  T. Dawson,et al.  Molecular Pathways of Neurodegeneration in Parkinson's Disease , 2003, Science.

[3]  Andrew B West,et al.  Molecular pathophysiology of Parkinson's disease. , 2005, Annual review of neuroscience.

[4]  Cam Patterson,et al.  The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. , 2007, The Journal of clinical investigation.

[5]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[6]  T. Dawson,et al.  Diagnosis and treatment of Parkinson disease: molecules to medicine. , 2006, The Journal of clinical investigation.

[7]  P. Connell,et al.  Identification of CHIP, a Novel Tetratricopeptide Repeat-Containing Protein That Interacts with Heat Shock Proteins and Negatively Regulates Chaperone Functions , 1999, Molecular and Cellular Biology.

[8]  D. Cyr,et al.  The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation , 2000, Nature Cell Biology.

[9]  Robert L. Nussbaum,et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease , 1997 .

[10]  Holly McDonough,et al.  CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70 , 2006, Nature.

[11]  M. Farrer,et al.  Lrrk2 R1441 substitution and progressive supranuclear palsy , 2006, Neuropathology and applied neurobiology.

[12]  D. Cyr,et al.  Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. , 2002, Trends in biochemical sciences.

[13]  H. Cai,et al.  The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2 , 2008, The Journal of Neuroscience.

[14]  M. Cookson,et al.  The Parkinson Disease-associated Leucine-rich Repeat Kinase 2 (LRRK2) Is a Dimer That Undergoes Intramolecular Autophosphorylation* , 2008, Journal of Biological Chemistry.

[15]  P. Connell,et al.  The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins , 2000, Nature Cell Biology.

[16]  L. Neckers,et al.  Heat shock protein 90: The cancer chaperone , 2007, Journal of Biosciences.

[17]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[18]  D. Cyr,et al.  CHIP Is a U-box-dependent E3 Ubiquitin Ligase , 2001, The Journal of Biological Chemistry.

[19]  K. Lim,et al.  Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. , 2007, Human molecular genetics.

[20]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[21]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[22]  C. Ross,et al.  Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  W. Dauer,et al.  Parkinson's Disease Mechanisms and Models , 2003, Neuron.

[24]  C. Ross,et al.  Kinase activity of mutant LRRK2 mediates neuronal toxicity , 2006, Nature Neuroscience.

[25]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[26]  Janel O. Johnson,et al.  Clinical and positron emission tomography of Parkinson's disease caused by LRRK2 , 2005, Annals of neurology.

[27]  Reidun Torp,et al.  Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis. , 2005, Human molecular genetics.

[28]  A. Singleton,et al.  Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. , 2005, Brain : a journal of neurology.

[29]  Andrew B West,et al.  Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Kazuko Hasegawa,et al.  An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family , 2005, Annals of neurology.

[31]  I. Marín.  The Parkinson disease gene LRRK2: evolutionary and structural insights. , 2006, Molecular biology and evolution.

[32]  Hongjun Song,et al.  Accumulation of the Authentic Parkin Substrate Aminoacyl-tRNA Synthetase Cofactor, p38/JTV-1, Leads to Catecholaminergic Cell Death , 2005, The Journal of Neuroscience.

[33]  P. Emson,et al.  Localization of LRRK2 to membranous and vesicular structures in mammalian brain , 2006, Annals of neurology.

[34]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[35]  M. Farrer,et al.  LRRK2 mutations in Parkinson disease , 2005, Neurology.

[36]  R. Koehler,et al.  Poly(ADP-ribose) (PAR) polymer is a death signal , 2006, Proceedings of the National Academy of Sciences.

[37]  T. Meitinger,et al.  The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. , 2006, Human molecular genetics.

[38]  L. Petrucelli,et al.  Brain CHIP: removing the culprits in neurodegenerative disease. , 2007, Trends in molecular medicine.

[39]  Nicholas W Wood,et al.  A common LRRK2 mutation in idiopathic Parkinson's disease , 2005, The Lancet.

[40]  P. V. van Haastert,et al.  Roc, a Ras/GTPase domain in complex proteins. , 2003, Biochimica et biophysica acta.

[41]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.