title: c-Abl-p38α signaling plays an important role in MPTP-induced neuronal death.
abstract: Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Abl-mediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: R
authors.initials: R
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Q
authors.initials: Q
authors.lastname: He
authors.affiliation: Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000595:Amino Acid Sequence; D000818:Animals; D016923:Cell Death; D059290:Dopaminergic Neurons / Q000502:physiology*; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism*; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D010302:Parkinson Disease, Secondary / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000068877:Imatinib Mesylate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D016315:Proto-Oncogene Proteins c-abl; D048308:Mitogen-Activated Protein Kinase 14