oa C-Abl Phosphorylates Alpha-synuclein And Regulates Its Degradation, Implication For Alpha-synuclein Clearance And Contribution To The Pathogenesis Of Parkinson's Disease

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 alpha-synuclein (alpha-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 alpha-syn is a bona fide substrate for c-Abl. In vitro studies demonstrate that c-Abl directly interacts with alpha-syn and catalyzes its phosphorylation mainly on tyrosine 39 (pY39), and to a lesser extent on tyrosine Y125 (pY125). Analysis of human brain tissues showed for the first time that pY39 alpha-syn is detected in the brains of healthy individuals and those with PD. Interestingly, whereas Nilotinib, a specific inhibitor of c-Abl kinase activity, induces alpha-syn protein degradation via the autophagy and proteasome pathways, the overexpression of alpha-syn in the midbrain of rats enhances c-Abl expression. Together, these results suggest that changes in c-Abl expression and/or activation play important roles in regulating alpha-syn clearance and contribute to the pathogenesis of PD. Thus, targeting c-Abl kinase activity represents a promising therapeutic strategy for the treatment of PD and related synucleinopathies. This work was funded by ERC, NIH (#R37-AG019391 and #R24AA012725) and the Swiss cancer league (KLS-3132-02-2013, KLS-3132-02-2013). Our work was recently published in Hum Mol Genet. 2014 Jun 1;23(11):2858-79.