C-Abl phosphorylates α-synuclein and regulates its degradation: Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease

Anne Laure Mahul-Mellier, Bruno Fauvet, Amanda Gysbers, Igor Dikiy, Abid Oueslati, Sandrine Georgeon, Allan J. Lamontanara, Alejandro Bisquertt, David Eliezer, Eliezer Masliah, Glenda Halliday, Oliver Hantschel, Hilal A. Lashuel

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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 a-synuclein (a-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 a-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established thata-syn is a bona fide substrate for c-Abl. In vitro studiesdemonstrate that c-Abl directly interacts with a-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 pY39a-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 α-syn protein degradation via the autophagy and proteasome pathways, whereas the overexpression of a-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 α-syn clearance and contribute to the pathogenesis of PD.

Original languageEnglish
Article numberddt674
Pages (from-to)2858-2879
Number of pages22
JournalHuman Molecular Genetics
Volume23
Issue number11
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Mahul-Mellier, A. L., Fauvet, B., Gysbers, A., Dikiy, I., Oueslati, A., Georgeon, S., Lamontanara, A. J., Bisquertt, A., Eliezer, D., Masliah, E., Halliday, G., Hantschel, O., & Lashuel, H. A. (2014). C-Abl phosphorylates α-synuclein and regulates its degradation: Implication for α-synuclein clearance and contribution to the pathogenesis of parkinson's disease. Human Molecular Genetics, 23(11), 2858-2879. [ddt674]. https://doi.org/10.1093/hmg/ddt674