title: c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-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 α-synuclein (α-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 α-syn toxicity and clearance remain unknown. Herein, using NMR spectroscopy, mass spectrometry, in vitro enzymatic assays and cell-based studies, we established that α-syn is a bona fide substrate for c-Abl. In vitro studies demonstrate that c-Abl directly interacts with α-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 α-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 α-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.
authors.affiliation: Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.forename: Bruno
authors.initials: B
authors.lastname: Fauvet
authors.forename: Amanda
authors.initials: A
authors.lastname: Gysbers
authors.forename: Igor
authors.initials: I
authors.lastname: Dikiy
authors.forename: Abid
authors.initials: A
authors.lastname: Oueslati
authors.forename: Sandrine
authors.initials: S
authors.lastname: Georgeon
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Lamontanara
authors.forename: Alejandro
authors.initials: A
authors.lastname: Bisquertt
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Glenda
authors.initials: G
authors.lastname: Halliday
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D059748:Proteolysis; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D016315:Proto-Oncogene Proteins c-abl