C-Abl phosphorylates ?-synuclein and regulates its degradation: implication for ?-synuclein clearance and contribution to the pathogenesis of Parkinson's disease.

ABSTRACT: Increasing evidence suggests that the c-Abl protein tyrosine kinase could play a role in the pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. c-Abl has been shown to regulate the degradation of two proteins implicated in the pathogenesis of PD, parkin and ?-synuclein (?-syn). The inhibition of parkin's neuroprotective functions is regulated by c-Abl-mediated phosphorylation of parkin. However, the molecular mechanisms by which c-Abl activity regulates ?-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established that ?-syn is a bona fide substrate for c-Abl. In vitro studies demonstrate that c-Abl directly interacts with ?-syn and catalyzes its phosphorylation mainly at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39 ?-syn is detected in the brains of healthy individuals and those with PD. However, only c-Abl protein levels were found to be upregulated in PD brains. Interestingly, nilotinib, a specific inhibitor of c-Abl kinase activity, induces ?-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of ?-syn in the rat midbrains enhances c-Abl expression. Together, these data suggest that changes in c-Abl expression, activation and/or c-Abl-mediated phosphorylation of Y39 play a role in regulating ?-syn clearance and contribute to the pathogenesis of PD.

SUBMITTER: Mahul-Mellier AL 

PROVIDER: S-EPMC4014189 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature