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应激颗粒，FUS相关肌萎缩侧索硬化症的治疗新靶点
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Abstract:
肌萎缩侧索硬化症(amyotrophic lateral sclerosis, ALS)是一种引起上、下运动神经元退化的神经退行性疾病，其病理学的确切机制尚不清楚。与ALS相关的病理过程包括线粒体功能障碍、蛋白质稳态失衡和RNA代谢缺陷。在ALS患者退化的运动神经元中FUS蛋白形成了不溶性聚集体，而ALS相关的FUS突变加速了该过程。近年来很多研究表明，应激颗粒(stress granules, SGs)在FUS突变引起蛋白病变并驱动ALS进展的过程中发挥了重要作用。SGs是真核细胞响应压力形成的一种动态无膜细胞器，主要包含暂停翻译的mRNA和RNA结合蛋白。SGs通过招募mRNA调控了翻译，通过招募信号分子调控了信号通路，从而促进了细胞在压力下的适应和存活。然而，多种慢性压力诱导的SGs具有致病作用。SGs被认为在很多神经退行性疾病病理性蛋白质聚集体的产生过程中发挥了“成核种子”的作用，包括FUS突变引起的蛋白质聚集体。本文主要就SGs在FUS相关ALS病理发生中的作用及其靶向治疗策略做一简要概述和讨论。
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes degeneration of upper and lower motor neurons. The exact mechanisms underlying the pathogenesis of ALS remain elusive. Many pathological processes are associated with ALS, including mitochondrial dysfunction, loss of proteostasis and defect in RNA metabolism. FUS protein develops insoluble aggregation in degenerated motor neurons of ALS patients, which is accelerated by ALS-linked FUS mutations. Recently, many studies have shown that stress granules (SGs) play an important role in proteinopathy of mutated FUS that drives ALS progression. SGs are stress-induced dynamic membraneless organelle in eukaryotic cells, containing translation-stalled mRNAs and RNA binding proteins. SGs regulate mRNA translation and signaling pathways by recruitment of mRNAs and signaling proteins respectively, leading to stress adaption and cell survival. However, SGs induced by some chronic stress exert pathological outcomes and are believed to act as a seed for the formation of pathological protein aggregation in many neurodegenerative diseases, including FUS mutations-induced protein aggregation. Here we briefly summarized and discussed the role of SGs in the pathogenesis of FUS-re- lated ALS and the therapeutic strategy targeting SGs.
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