TRIM16在肌萎缩侧索硬化症中的保护作用及机制研究

肌萎缩侧索硬化症（ALS）是一种以运动神经元变性死亡为主要特征的神经退行性疾病。TDP-43是ALS患者特征性的病理聚集蛋白，是引起运动神经元变性死亡的主要机制。TRIM16可促进蛋白聚集体的降解，抵抗氧化应激导致的细胞损伤。我们研究发现TDP-43 M337V细胞中TRIM16水平降低，逆转TRIM16后细胞的存活率提升，氧化应激损伤改善。由此我们提出科学假说：TRIM16是ALS发病机制中的关键因素，其缺失导致Nrf2抗氧化信号通路异常，影响TDP-43蛋白降解，最终引起运动神经变性死亡。本项目以TRIM16为靶点，采用细胞和动物模型，系统研究TRIM16对TDP-43异常蛋白聚集所致神经元损伤的保护作用，明确TRIM16调控TDP-43蛋白聚集体降解的途径及机制，并对Nrf2抗氧化通路在其中的作用进行探讨。为ALS发病机制的阐明提供新的理论依据，更为ALS药物研发提供新思路和新靶点。

Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive neurodegenerative disease characterized by degeneration of upper and lower motor neurons. The common neuropathological marker in over 95% of cases of both sporadic and familial ALS is the redistribution of the protein TDP-43 (43-kDa transactive response DNA-binding protein) from a predominantly nuclear localization to form insoluble ubiquitinated aggregates in the cytoplasm of affected motor neurons. Altered TDP-43 function and distribution is considered as a primary pathogenesis of ALS. The recent study reported that TRIM16 activated ubiquitin pathway genes and p62, leading to ubiquitination of misfolded proteins and formation of protein aggregates, and then induced aggregate clearance and protected cells against oxidative-induced toxicity. My lab found that the expression of TRIM16 was decreased in TDP-43 M337V transfected NSC-34 cells. However, the overexpression of TRIM16 could reverse the TDP-43-induced cell survival reduction, and decrease oxidative damage. Taken together, TRIM16 might be involved in the pathogenesis of ALS..In the present project, we will observe the protective effects of TRIM16 in NSC-34 cells transfected by TDP-43 M337V. Then, we will investigate the role of TRIM16 on TDP-43 abnormal aggregation. Lastly, the mechanisms of TRIM16 regulating TDP-43-indcuecd neuronal damage will be detected. The study will provide strong scientific evidences to reveal the function of TRIM16 in ALS. The project will contribute to further clarify the pathogenesis of ALS, and provide a novel illustration for the protective effect of TRIM16 against ALS. It may offer a possible new target for ALS treatment.