title: Arsenite stress down-regulates phosphorylation and 14-3-3 binding of leucine-rich repeat kinase 2 (LRRK2), promoting self-association and cellular redistribution.
abstract: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson disease, but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at Ser(910)/Ser(935) mediates interaction with 14-3-3. Pharmacological inhibition of its kinase activity abolishes Ser(910)/Ser(935) phosphorylation and 14-3-3 binding, and this effect is also mimicked by pathogenic mutations. However, physiological situations where dephosphorylation occurs have not been defined. Here, we show that arsenite or H2O2-induced stresses promote loss of Ser(910)/Ser(935) phosphorylation, which is reversed by phosphatase inhibition. Arsenite-induced dephosphorylation is accompanied by loss of 14-3-3 binding and is observed in wild type, G2019S, and kinase-dead D2017A LRRK2. Arsenite stress stimulates LRRK2 self-association and association with protein phosphatase 1α, decreases kinase activity and GTP binding in vitro, and induces translocation of LRRK2 to centrosomes. Our data indicate that signaling events induced by arsenite and oxidative stress may regulate LRRK2 function.
authors.affiliation: From the Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, United Kingdom, the Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BJ, United Kingdom, the Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892, adamantios.mamais@nih.gov.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.affiliation: the Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892, the Department of Neuroscience, Georgetown University Medical Center, Washington, D. C. 20057.
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.affiliation: the Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.affiliation: the Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892, the Brown University/National Institutes of Health Graduate Partnership Program, Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: David N
authors.initials: DN
authors.lastname: Hauser
authors.affiliation: the Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BJ, United Kingdom.
authors.forename: Christine
authors.initials: C
authors.lastname: Hall
authors.affiliation: the Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BJ, United Kingdom, the School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AP, United Kingdom.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Lewis
authors.affiliation: the Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.affiliation: From the Reta Lila Weston Institute of Neurological Studies, University College London Institute of Neurology, London WC1N 1PJ, United Kingdom, the Department of Molecular Neuroscience, University College London Institute of Neurology, London WC1N 3BJ, United Kingdom, rina.bandopadhyay@ucl.ac.uk.
authors.forename: Rina
authors.initials: R
authors.lastname: Bandopadhyay
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D018053:Arsenites / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D048948:14-3-3 Proteins; D018053:Arsenites; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; C015001:arsenite
keywords: Arsenite; Leucine-rich Repeat Kinase 2 (LRRK2); Neurodegenerative Disease; Oxidative Stress; Parkinson Disease; Phosphorylation