Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1
Autophagy and Ubiquitin-Proteasome System Coordinate to Regulate the Protein Quality Control of Neurodegenerative Disease-Associated DCTN1
复制标题
自噬和泛素蛋白酶体系统协调调节神经退行性疾病相关 DCTN1 的蛋白质质量控制
DOI：
10.1007/s12640-019-00113-y
复制
发表时间：
2019
影响因子：
3.7
通讯作者：
Wang Hongfeng
中科院分区：
文献类型：
--
作者：
Wang Nana;Ma Qilian;Peng Panpan;Yu Yunhao;Xu Shiqiang;Wang Guanghui;Ying Zheng;Wang Hongfeng
运动神经元病是以中枢神经系统上下运动神经元变性为特征的神经退行性疾病。Dynactin 1(DCTN1)是Dynein/dynactin运动复合体中的一种成分，此前已被发现会导致运动神经元疾病和其他神经退行性疾病。最近的研究表明，运动神经元疾病相关突变，如G59S突变，可导致DCTN1功能障碍和蛋白聚集。然而，参与清除DCTN1聚集体的细胞途径仍未完全阐明。在这项研究中，我们采用了DCTN1连锁神经变性的培养细胞模型，并探索了细胞蛋白控制系统在调节野生型和突变型DCTN1中的作用。我们发现，在正常情况下，泛素-蛋白酶体系统是野生型和G59S DCTN1周转的主要蛋白质降解系统，而不是自噬。然而，事实证明，当蛋白酶体活性受到抑制时，自噬可以在清除G59S DCTN1蛋白聚集体中发挥作用。重要的是，TFEB的过表达是自噬的主要调节因子，当蛋白酶体受损时，TFEB的过表达促进了G59S DCTN1聚集体的自噬清除，并缓解了G59S DCTN1诱导的细胞毒性。综上所述，当蛋白酶体功能受损时，自噬可能起到备用系统的作用，以保护细胞免受易于聚集的DCTN1引起的细胞毒性。
Motor neuron diseases are neurodegenerative diseases that are characterized by degeneration of the upper and lower motor neurons in the central nervous system. Mutations in Dynactin 1 (DCTN1), a component in the Dynein/Dynactin motor complex, have been previously identified to cause motor neuron diseases and other neurodegenerative disorders. Recent studies showed that motor neuron disease-linked mutation, such as G59S mutation, could lead to dysfunction and protein aggregation of DCTN1. However, the cellular pathway involved in the clearance of DCTN1 aggregates is still not fully elucidated. In this study, we employed a culture cell model of DCTN1-linked neurodegeneration and explored the role of cellular protein control systems in the regulation of wild type and mutant DCTN1. We find that the ubiquitin-proteasome system, but not autophagy, is the primary protein degradation system for the turnover of both wild type and G59S DCTN1 under normal conditions. However, it turns out that autophagy can play a role in the clearance of protein aggregates of G59S DCTN1 when the proteasome activity is inhibited. Importantly, overexpression of TFEB, a master regulator of autophagy, promotes the autophagic clearance of G59S DCTN1 aggregates and ameliorates G59S DCTN1-induced cytotoxicity when the proteasomes are impaired. In conclusion, autophagy may play as a backup system to protect cells against the cytotoxicity induced by aggregate-prone DCTN1 when proteasomal function is damaged.