Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease.
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.
Mesh Terms:
Acetylcysteine, Animals, Brain, Case-Control Studies, Cell Line, Disease Models, Animal, Dopamine, Drug Administration Schedule, Free Radical Scavengers, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Immunoprecipitation, MPTP Poisoning, Male, Metalloporphyrins, Mice, Mice, Inbred C57BL, Oxidative Stress, Peptide Elongation Factors, Phosphorylation, Piperazines, Polyethylene Glycols, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-abl, Pyrimidines, RNA, Small Interfering, Statistics, Nonparametric, Transfection, Tumor Suppressor Proteins, Tyrosine, Ubiquitin-Protein Ligases, Ubiquitination
Acetylcysteine, Animals, Brain, Case-Control Studies, Cell Line, Disease Models, Animal, Dopamine, Drug Administration Schedule, Free Radical Scavengers, Gene Expression Regulation, Green Fluorescent Proteins, Humans, Immunoprecipitation, MPTP Poisoning, Male, Metalloporphyrins, Mice, Mice, Inbred C57BL, Oxidative Stress, Peptide Elongation Factors, Phosphorylation, Piperazines, Polyethylene Glycols, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-abl, Pyrimidines, RNA, Small Interfering, Statistics, Nonparametric, Transfection, Tumor Suppressor Proteins, Tyrosine, Ubiquitin-Protein Ligases, Ubiquitination
J. Neurosci.
Date: Jan. 05, 2011
PubMed ID: 21209200
View in: Pubmed Google Scholar
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