Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease.
Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease.
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DOI：
10.1523/jneurosci.1833-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
--
通讯作者：
Li S
中科院分区：
文献类型：
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作者：
Imam SZ;Zhou Q;Yamamoto A;Valente AJ;Ali SF;Bains M;Roberts JL;Kahle PJ;Clark RA;Li S
Parkin是一种E3泛素连接酶，它的突变是常染色体隐性遗传性帕金森病(PD)的最常见原因。在这里，我们证明了压力信号非受体酪氨酸激酶c-Abl通过酪氨酸磷酸化将parkin与散发性帕金森病联系起来。在氧化应激和多巴胺能应激条件下，成年C57小鼠培养的神经细胞和纹状体中的c-Abl被激活。帕金森病患者纹状体内c-Abl呈活化状态。与此同时，parkin被酪氨酸磷酸化，导致其泛素连接酶和细胞保护活性的丧失，并导致parkin底物AIMP2(p38/JTV-1)和FBP-1的积累。选择性c-Abl抑制剂STI-571在体内外均能抑制parkin的酪氨酸磷酸化，恢复其E3连接酶活性和细胞保护功能。我们的结果表明，c-Abl对parkin的酪氨酸磷酸化是导致散发性帕金森病患者parkin功能丧失和疾病进展的主要翻译后修饰。此外，c-Abl的抑制为阻断PD进展提供了新的治疗机会。
Mutations in parkin, an E3 ubiquitin ligase, are most common cause of autosomal-recessive Parkinson's disease (PD). Here, we show that the stress-signaling non-receptor tyrosine-kinase c-Abl links parkin to sporadic forms of PD via tyrosine phosphorylation. Under oxidative and dopaminergic stress, c-Abl was activated in cultured neuronal cells and in striatum of adult C57 mice. Activated c-Abl was found in the striatum of PD patients. Concomitantly, parkin was tyrosine-phosphorylated, causing loss ofit's ubiquitin ligase and cytoprotective activities, and the accumulation of parkin substrates, AIMP2 (p38/JTV-1) and FBP-1. STI-571, a selective c-Abl inhibitor, prevented tyrosine phosphorylation of parkin and restored its E3 ligase activity and cytoprotective function both in vitro and in vivo. Our results suggest that tyrosine phosphorylation of parkin by c-Abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic PD. Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression.