靶向于SIRT2的转录后调节在帕金森病神经保护中的作用及机制研究

Sirtuins (silent information regulator 2-related enzyme) are NAD-dependent protein deacetylases that were shown to participate in age-related diseases. SIRT2 is a strong deacetylase that is highly expressed in brain. In initial study, we found SIRT2 protein was increased in PD, independent with mRNA change. Recently, we found miR-212-5p was decreased in PD, which targets SIRT2 by biological prediction. PD is characterized by dopamic neuron processing loss. p53 dependent cell death, deacetylased by SIRT2, play a key role in PD pathology. In this study, we intend to investigate the post-transcriptional regulation of SIRT2 and the mechanism of p53 dependent autophagy in PD with miR-212-5p transgenic mice both in vivo and in vitro. We propose that SIRT2 involves the pathogenesis of PD via regulating autophagy by p53 deacetylation. These findings will give as an insight into potential of SIRT2 in neuroprotection of PD.

SIRT2是酵母沉默信息调节子2（silent information regulator2, Sir2）相关酶类的一个亚型，是重要的组氨酸去乙酰化酶，参与老龄化相关疾病。申请者所在实验室前期发现PD（Parkinson’s disease）中SIRT2蛋白表达显著升高，而未见转录水平变化；miR-212-5p在PD纹状体表达显著下调，且预测SIRT2是miR-212-5p的潜在靶基因。以上结果提示我们SIRT2存在转录后调节。多巴胺能神经元进行性丢失是PD特征，SIRT2对下游底物的去乙酰化作用引起细胞死亡参与PD的发生发展。本研究拟在原有工作基础上，应用miR-212-5p转基因小鼠，在整体和分子水平系统研究、阐明SIRT2的转录后调节及机制，揭示SIRT2对于p53去乙酰化作用依赖的细胞自噬在PD发生发展中的作用。研究结果将有助于补充PD发病机制，研发靶向于SIRT2的神经保护剂。

沉默信息调节子2相关蛋白2（silent information regulator 2 related protein 2, SIRT2）是一种重要的组氨酸去乙酰化酶，其通过对下游底物的去乙酰化作用，参与包括帕金森病（Parkinson’s disease，PD）在内的多种老化相关疾病。文献报道，抑制SIRT2活性能够在PD模型中发挥神经保护作用，然而目前的SIRT2抑制剂缺乏特异性。本研究发现PD模型小鼠中脑SIRT2蛋白表达显著升高，而未见转录水平变化；miR-212-5p在PD模型小鼠中脑表达显著下调；通过生物信息学预测及双荧光素酶报告基因证实SIRT2是miR-212-5p的潜在靶基因。以上结果提示我们SIRT2可能通过转录后调节参与PD病理进展。多巴胺能神经元进行性丢失是PD病理特征，我们推测SIRT2通过对其下游底物p53的去乙酰化作用影响p53依赖的程序性细胞死亡从而参与PD发生。进一步研究发现，受miR-212-5p调控的SIRT2通过调节p53胞核胞浆的分布，从而影响p53依赖的PD模型中神经元自噬和凋亡。本研究结果表明，在PD模型中SIRT2高表达且受miR-212-5p的转录后调节，并揭示了SIRT2对于p53去乙酰化作用依赖的细胞自噬和凋亡在PD发生中的作用。本研究结果将有助于补充PD发病机制，研发靶向于SIRT2的神经保护剂。