Mahul-Mellier Anne-Laure, Fauvet Bruno, Gysbers Amanda, Dikiy Igor, Oueslati Abid, Georgeon Sandrine, Lamontanara Allan J, Bisquertt Alejandro, Eliezer David, Masliah Eliezer, Halliday Glenda, Hantschel Oliver, Lashuel Hilal A
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute.
Hum Mol Genet. 2014 Jun 1;23(11):2858-79. doi: 10.1093/hmg/ddt674. Epub 2014 Jan 9.
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.
越来越多的证据表明，c-Abl蛋白酪氨酸激酶可能在帕金森病（PD）和其他神经退行性疾病的发病机制中发挥作用。c-Abl已被证明可调节与PD发病机制相关的两种蛋白质——帕金蛋白和α-突触核蛋白（α-syn）的降解。帕金蛋白的神经保护功能抑制是由c-Abl介导的帕金蛋白磷酸化调节的。然而，c-Abl活性调节α-syn毒性和清除的分子机制仍不清楚。在此，我们使用核磁共振光谱、质谱、体外酶促试验和基于细胞的研究，确定α-syn是c-Abl的真正底物。体外研究表明，c-Abl直接与α-syn相互作用，并主要在酪氨酸39（pY39）处催化其磷酸化，在较小程度上在酪氨酸125（pY125）处催化。对人脑组织的分析表明，在健康个体和PD患者的大脑中均检测到pY39 α-syn。然而，仅发现PD大脑中的c-Abl蛋白水平上调。有趣的是，c-Abl激酶活性的特异性抑制剂尼洛替尼通过自噬和蛋白酶体途径诱导α-syn蛋白降解，而大鼠中脑中α-syn的过表达增强c-Abl表达。总之，这些数据表明，c-Abl表达、激活和/或Y39的c-Abl介导的磷酸化变化在调节α-syn清除中起作用，并有助于PD的发病机制。
