The Critical Role of SIRT1 in Parkinson's Disease: Mechanism and Therapeutic Considerations.
The Critical Role of SIRT1 in Parkinson's Disease: Mechanism and Therapeutic Considerations.
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DOI：
10.14336/ad.2020.0216
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发表时间：
2020-12
影响因子：
7.4
通讯作者：
Wu YC
中科院分区：
文献类型：
--
作者：
Li X;Feng Y;Wang XX;Truong D;Wu YC
沉默信息调节因子1 （silent information regulator 1, SIRT1）是sirtuin家族的一员，其作用靶点是组蛋白和许多非组蛋白，参与多种生理功能。帕金森病（PD）患者SIRT1酶活性降低，这可能降低了他们抵抗各种神经毒素引起的神经元损伤的能力。据我们所知，SIRT1通过调节amp活化蛋白激酶、轻链3、哺乳动物雷帕霉素靶蛋白、叉头转录因子1等自噬相关蛋白诱导自噬。此外，SIRT1主要通过维持过氧化物酶体增殖体激活受体-γ共激活因子-1α (PGC-1α)处于去乙酰化状态，从而维持PGC-1α的稳定水平，从而调节线粒体功能，抑制氧化应激。其他研究表明SIRT1可能通过调节神经炎症在PD的病理生理中发挥作用。SIRT1使核因子κ B去乙酰化，从而降低其转录活性，抑制诱导型一氧化氮合酶的表达，降低肿瘤坏死因子- α和白细胞介素-6水平。SIRT1还可以通过去乙酰化热休克因子1上调热休克蛋白70，增加α-突触核蛋白低聚物的降解。很少有研究关注SIRT1单核苷酸多态性与PD风险的关系，因此这一课题需要进一步研究。基于SIRT1对PD的神经保护作用，许多体外和体内实验表明，一些SIRT1激活剂，特别是白藜芦醇，对各种神经毒素引起的多巴胺能神经元损伤具有潜在的神经保护作用。因此，SIRT1在帕金森病的发展中起着关键作用，可能是帕金森病治疗的潜在靶点。
Silence information regulator 1 (SIRT1), a member of the sirtuin family, targets histones and many non-histone proteins and participates in various physiological functions. The enzymatic activity of SIRT1 is decreased in patients with Parkinson’s disease (PD), which may reduce their ability to resist neuronal damage caused by various neurotoxins. As far as we know, SIRT1 can induce autophagy by regulating autophagy related proteins such as AMP-activated protein kinase, light chain 3, mammalian target of rapamycin, and forkhead transcription factor 1. Furthermore, SIRT1 can regulate mitochondrial function and inhibit oxidative stress mainly by maintaining peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in a deacetylated state and thus maintaining a constant level of PGC-1α. Other studies have demonstrated that SIRT1 may play a role in the pathophysiology of PD by regulating neuroinflammation. SIRT1 deacetylases nuclear factor-kappa B and thus reduces its transcriptional activity, inhibits inducible nitric oxide synthase expression, and decreases tumor necrosis factor-alpha and interleukin-6 levels. SIRT1 can also upregulate heat shock protein 70 by deacetylating heat shock factor 1 to increase the degradation of α-synuclein oligomers. Few studies have focused on the relationship between SIRT1 single nucleotide polymorphisms and PD risk, so this topic requires further research. Based on the neuroprotective effects of SIRT1 on PD, many in vitro and in vivo experiments have demonstrated that some SIRT1 activators, notably resveratrol, have potential neuroprotective effects against dopaminergic neuronal damage caused by various neurotoxins. Thus, SIRT1 plays a critical role in PD development and might be a potential target for PD therapy.