| First Author | Mahul-Mellier AL | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 11 | Pages | 2858-79 |
| PubMed ID | 24412932 | Mgi Jnum | J:210101 |
| Mgi Id | MGI:5569562 | Doi | 10.1093/hmg/ddt674 |
| Citation | Mahul-Mellier AL, et al. (2014) c-Abl phosphorylates alpha-synuclein and regulates its degradation: implication for alpha-synuclein clearance and contribution to the pathogenesis of Parkinson's disease. Hum Mol Genet 23(11):2858-79 |
| abstractText | 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 alpha-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 at tyrosine 39 (pY39) and to a lesser extent at tyrosine 125 (pY125). Analysis of human brain tissues showed that pY39 alpha-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 alpha-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of alpha-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 alpha-syn clearance and contribute to the pathogenesis of PD. |
