Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models
Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models
复制标题
在帕金森病模型中，Cdk5 抑制通过泛素蛋白酶体途径阻止 SIRT1 降解
DOI：
10.1016/j.bbagen.2018.03.021
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发表时间：
2018
影响因子：
3
通讯作者：
Tian Bo
中科院分区：
文献类型：
--
作者：
Zhang Qian;Zhang Pei;Qi Guang Jian;Zhang Zheng;He Feng;Lv Ze Xi;Peng Xiang;Cai Hong Wei;Li Tong Xia;Wang Xue Min;Tian Bo
NAD+依赖性蛋白去乙酰化酶sirtuin 1 （SIRT1）是sirtuin家族的一名成员，可能对阿尔茨海默病（AD）、帕金森病（PD）和肌萎缩侧索硬化症（ALS）等多种神经退行性疾病具有神经保护作用。许多研究表明，过表达诱导或白藜芦醇处理的SIRT1激活可以显著改善小鼠模型中的几种神经退行性疾病。然而，SIRT1的类型、蛋白表达水平和潜在机制尚不清楚，特别是在PD中。本研究结果表明，SIRT1敲除显著恶化mptp损伤PD动物模型的运动功能。SIRT1的表达不仅在环境因子PD模型、神经毒素MPP+处理的原代培养神经元和mptp诱导的小鼠中显著降低，而且在遗传因子PD模型、过表达α-synuclein-A30PA53T SH-SY5Y稳定细胞系和hm2α-SYN-39转基因小鼠株中也明显降低。重要的是，MPP+处理过程中SIRT1的降解是通过泛素-蛋白酶体途径介导的。此外，研究结果表明，细胞周期蛋白依赖性激酶5 （cyclin-dependent kinase 5, Cdk5）也参与SIRT1表达的降低，而抑制Cdk5可以有效阻断SIRT1的表达。总之，我们的研究结果表明，cdk5依赖性泛素蛋白酶体途径介导的SIRT1降解在PD的进展中起着至关重要的作用。
The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP+-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm2α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP+treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD.