title: Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease.
abstract: Mutations in parkin, an E3 ubiquitin ligase, are the most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57BL/6 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates, AIMP2 (aminoacyl tRNA synthetase complex-interacting multifunctional protein 2) (p38/JTV-1) and FBP-1.STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA. imam@uthscsa.edu
authors.forename: Syed Z
authors.initials: SZ
authors.lastname: Imam
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Valente
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.forename: Mona
authors.initials: M
authors.lastname: Bains
authors.forename: James L
authors.initials: JL
authors.lastname: Roberts
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Robert A
authors.initials: RA
authors.lastname: Clark
authors.forename: Senlin
authors.initials: S
authors.lastname: Li
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000494:pharmacology; D004334:Drug Administration Schedule; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D047468:Immunoprecipitation / Q000379:methods; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010445:Peptide Elongation Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000633:toxicity; D011092:Polyethylene Glycols / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity; D034741:RNA, Small Interfering / Q000494:pharmacology; D018709:Statistics, Nonparametric; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D001549:Benzamides; C529799:EEF1E1 protein, human; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D010445:Peptide Elongation Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; C551282:polyethylene glycol monooctylphenyl ether; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D014443:Tyrosine; D000068877:Imatinib Mesylate; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D016315:Proto-Oncogene Proteins c-abl; D004298:Dopamine; D000111:Acetylcysteine