PGC-1α/ERRα-Sirt3 pathway regulates DAergic neuronal death by directly deacetylating SOD2 and ATP synthase β
PGC-1α/ERRα-Sirt3 pathway regulates DAergic neuronal death by directly deacetylating SOD2 and ATP synthase β
复制标题
PGC-1alpha/ERRalpha-Sirt3 通路通过直接去乙酰化 SOD2 和 ATP 合成酶 beta 来调节 DAergic 神经元死亡。
DOI：
10.1089/ars.2015.6403
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Ji J
中科院分区：
文献类型：
--
作者：
C Wang;Cao L;Wang Q;Ji J
摘要目的：帕金森病(Parkinson‘s Disease，PD)严重影响人类健康，其病因和发病机制尚不清楚。Sirtuin3(SIRT3)在调节线粒体功能障碍中起着关键作用，线粒体功能障碍是帕金森病患者DAR能神经元丢失的主要原因。我们探讨了SIRT3在DAR能神经元存活中的神经保护作用机制。结果：在1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)处理的神经元中，SIRT3的过度表达具有神经保护作用。我们发现SIRT3与超氧化物歧化酶和三磷酸腺苷合成酶β相互作用，并通过去乙酰化超氧化物歧化酶K130和三磷酸腺苷合成酶β来调节它们的活性，以防止活性氧的积累和三磷酸腺苷的耗竭，并减轻MPTP处理后神经元的死亡。过氧化物酶体增殖物激活受体-γ共激活因子1α(PGC-1α)与雌激素相关受体α(Errα)相互作用，作为转录因子与SIRT3启动子结合，调节细胞周期。
Abstract Aims: Parkinson's disease (PD) heavily affects humans and little is known about its cause and pathogenesis. Sirtuin 3 (Sirt3) plays a key role in regulating mitochondrial dysfunction, which is the main cause of DAergic neuronal loss in PD. We investigated the mechanisms of neuroprotective role of Sirt3 in DAergic neuronal survival. Results: Sirt3 was reduced in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated neurons with its overexpression being neuroprotective. We identified that Sirt3 interacted with manganese superoxide dismutase (SOD2) and adenosine triphosphate (ATP) synthase β and modulated their activities by deacetylating SOD2 (K130) and ATP synthase β (K485) to prevent reactive oxygen species accumulation and ATP depletion, and to alleviate DAergic neuronal death upon MPTP treatment. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) interacted with estrogen-related receptor alpha (ERRα) that bound to the Sirt3 promoter as its transcription factor to regulat...