c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson's disease
c-Abl phosphorylates α-synuclein and regulates its degradation: implication for α-synuclein clearance and contribution to the pathogenesis of Parkinson's disease
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DOI：
10.1093/hmg/ddt674
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发表时间：
2014-06-01
影响因子：
3.5
通讯作者：
Lashuel, Hilal A.
中科院分区：
文献类型：
--
作者：
Mahul-Mellier, Anne-Laure;Fauvet, Bruno;Lashuel, Hilal A.
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已显示调节参与PD发病机制的两种蛋白质parkin和α-突触核蛋白（α-syn）的降解。parkin的神经保护功能的抑制受c-Abl介导的parkin磷酸化的调节。然而，c-Abl活性调节α-syn毒性和清除的分子机制仍然未知。在此，我们利用核磁共振光谱、质谱、体外酶分析和基于细胞的研究，确定了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，并催化其磷酸化，主要在酪氨酸39（pY 39）和酪氨酸125（pY 125）。对人脑组织的分析表明，在健康个体和PD患者的大脑中检测到pY 39 α-syn。然而，只有c-Abl蛋白水平被发现在PD脑中上调。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的过表达增强了c-Abl的表达。总之，这些数据表明，c-Abl表达、激活和/或c-Abl介导的Y39磷酸化的变化在调节α-syn清除中起作用，并有助于PD的发病机制。
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.