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Cell Death Differ. 2016 Mar;23(3):542-52. doi: 10.1038/cdd.2015.135. Epub 2015 Oct 30.

c-Abl-p38α signaling plays an important role in MPTP-induced neuronal death.

Wu R1,2, Chen H1,3, Ma J1,2, He Q1,2, Huang Q4, Liu Q5, Li M4, Yuan Z1,2,3.

Author information

1
State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
2
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
3
Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
4
Department of Pharmacology and the Proteomics Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
5
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, China.

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.

PMID:
26517532
PMCID:
PMC5072446
[Available on 2017-03-01]
DOI:
10.1038/cdd.2015.135
[Indexed for MEDLINE]
Free PMC Article

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