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首页> 外文期刊>Molecular and Cellular Biology >Sestrin2 Protects Dopaminergic Cells against Rotenone Toxicity through AMPK-Dependent Autophagy Activation
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Sestrin2 Protects Dopaminergic Cells against Rotenone Toxicity through AMPK-Dependent Autophagy Activation

机译：Sestrin2通过依赖AMPK的自噬激活保护多巴胺能细胞免受鱼藤酮毒性

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Dysfunction of the autophagy-lysosomal pathway (ALP) and the ubiquitin-proteasome system (UPS) was thought to be an important pathogenic mechanism in synuclein pathology and Parkinson's disease (PD). In the present study, we investigated the role of sestrin2 in autophagic degradation of α-synuclein and preservation of cell viability in a rotenone-induced cellular model of PD. We speculated that AMP-activated protein kinase (AMPK) was involved in regulation of autophagy and protection of dopaminergic cells against rotenone toxicity by sestrin2. The results showed that both the mRNA and protein levels of sestrin2 were increased in a TP53-dependent manner in Mes 23.5 cells after treatment with rotenone. Genetic knockdown of sestrin2 compromised the autophagy induction in response to rotenone, while overexpression of sestrin2 increased the basal autophagy activity. Sestrin2 presumably enhanced autophagy in an AMPK-dependent fashion, as sestrin2 overexpression activated AMPK, and genetic knockdown of AMPK abrogated autophagy induction by rotenone. Restoration of AMPK activity by metformin after sestrin2 knockdown recovered the autophagy activity. Sestrin2 overexpression ameliorated α-synuclein accumulation, inhibited caspase 3 activation, and reduced the cytotoxicity of rotenone. These results suggest that sestrin2 upregulation attempts to maintain autophagy activity and suppress rotenone cytotoxicity through activation of AMPK, and that sestrin2 exerts a protective effect on dopaminergic cells.
机译：自噬溶酶体途径（ALP）和泛素-蛋白酶体系统（UPS）的功能异常被认为是突触核蛋白病理学和帕金森氏病（PD）的重要致病机制。在本研究中，我们研究了鱼藤酮诱导的PD细胞模型中sestrin2在α-突触核蛋白自噬降解和细胞活力保持中的作用。我们推测AMP激活的蛋白激酶（AMPK）参与调节自噬和保护多巴胺能细胞抵抗sestrin2对鱼藤酮的毒性。结果表明，鱼藤酮处理后，Mes 23.5细胞中sestrin2的mRNA和蛋白水平均以TP53依赖性方式增加。 sestrin2的基因敲低损害了对鱼藤酮的自噬诱导作用，而sestrin2的过表达增加了基础自噬活性。 Sestrin2可能以AMPK依赖性方式增强自噬，因为sestrin2过表达激活AMPK，而AMPK的基因敲除废除了鱼藤酮诱导的自噬。 sestrin2敲低后，通过二甲双胍恢复AMPK活性恢复了自噬活性。 Sestrin2过表达改善了α-突触核蛋白的积累，抑制了caspase 3的活化，并降低了鱼藤酮的细胞毒性。这些结果表明，sestrin2的上调试图通过激活AMPK来维持自噬活性并抑制鱼藤酮的细胞毒性，并且sestrin2对多巴胺能细胞具有保护作用。

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