CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress
CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress
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CDK5介导的Sirt2磷酸化导致社交失败压力诱发的抑郁样行为
DOI：
10.1016/j.bbadis.2017.11.012
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Tian Bo
中科院分区：
文献类型：
--
作者：
Zhang Zheng;Zhang Pei;Qi Guangjian;Jiao Fengjuan;Wang Qingzhi;Yan Jianguo;He Feng;Zhang Qian;Lv Zexi;Peng Xiang;Cai Hongwei;Chen Xiaoqian;Sun Ning;Tian Bo
重性抑郁障碍（Major Depression Disorder，MDD）是一种常见的、严重的、反复发作的精神疾病，其发病机制尚不清楚。组蛋白去乙酰化酶（HDAC）似乎在抑郁症中发挥重要作用。Sirt 1和Sirt 2作为III类HDAC，在神经系统中引起了最大的兴趣。事实上，慢性应激降低了Sirt 1活性，下调了Sirt 1基因在MDD中的表达。然而，关于Sirt 2的作用的文献很少。为了研究Sirt 2的作用，我们使用社交失败应激（SDS）在野生型和Sirt 2敲除的C57 BL/6小鼠中建立了MDD小鼠模型。我们发现，缺乏Sirt 2阻断了SDS诱导的抑郁样行为的发展。此外，SDS导致杏仁核中Sirt 2磷酸化而不改变总Sirt 2水平，并且通过CDK 5在丝氨酸残基368和372处阻断Sirt 2磷酸化防止SDS诱导的抑郁样行为和Sirt 2核输入。我们还发现SDS诱导的Sirt 2磷酸化参与了VTA-杏仁核的调节。这些结果表明，CDK 5介导杏仁核中Sirt 2的磷酸化，并有助于SDS诱导的抑郁样行为。这项研究强调，通过肉豆蔻酰化膜透化肽（Sirt 2-p）抑制Sirt 2在丝氨酸残基368和372处的CDK 5依赖性磷酸化，而不是使用非特异性sirtuin抑制剂，可能是治疗抑郁症的新策略。
Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.