Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Neurobiol Dis. 2020 Feb;134:104639. doi: 10.1016/j.nbd.2019.104639. Epub 2019 Oct 15.
Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, EWSR1, TAF15, hnRNPA1, hnRNPA2B1, ATXN2, TIA1) have been identified to interfere with SG formation through mutation of their low-complexity domain (LCD), and thereby cause or influence disease. Interestingly, disease pathways associated to the C9orf72 repeat expansion, the leading genetic cause of the FTD-ALS spectrum, intersect with SG-mediated protein aggregate formation. In this review, we provide a comprehensive overview of known SG proteins and their genetic contribution to the FTD-ALS spectrum. Importantly, multiple LCD-baring RBPs have already been identified in FTD-ALS that have not yet been genetically linked to disease. These should be considered candidate genes and offer opportunities for gene prioritization when mining sequencing data of unresolved FTD and ALS. Further, we zoom into the current understanding of the molecular processes of perturbed RBP function leading to disturbed SG dynamics, RNA metabolism, and pathological inclusions. Finally, we indicate how these gained insights open new avenues for therapeutic strategies targeting phase separation and SG dynamics to reverse pathological protein aggregation and protect against toxicity.
应激颗粒（SGs）是由 RNA 结合蛋白（RBPs）和 RNA 分子组成的动态无膜隔室，它们暂时组装在一起，使细胞能够通过停滞 mRNA 翻译并将合成转向细胞保护蛋白来应对细胞应激。异常的 SG 已成为额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）中有毒蛋白聚集引发的主要嫌疑对象。SG 动力学的紊乱似乎是由 RNA 结合蛋白（RBP）的改变介导的。事实上，越来越多的 FTD 和/或 ALS 相关的 RBP 编码基因（TDP43、FUS、EWSR1、TAF15、hnRNPA1、hnRNPA2B1、ATXN2、TIA1）已被确定通过其低复杂度结构域（LCD）的突变干扰 SG 的形成，从而导致或影响疾病。有趣的是，与 C9orf72 重复扩增相关的疾病途径，这是 FTD-ALS 谱的主要遗传原因，与 SG 介导的蛋白聚集体形成相交。在这篇综述中，我们提供了已知 SG 蛋白及其对 FTD-ALS 谱遗传贡献的全面概述。重要的是，在 FTD-ALS 中已经鉴定出多个尚未与疾病遗传相关的具有 LCD 的 RBP。这些应该被认为是候选基因，并在挖掘未解决的 FTD 和 ALS 的测序数据时提供基因优先级的机会。此外，我们深入研究了扰动的 RBP 功能导致 SG 动力学、RNA 代谢和病理包涵体紊乱的分子过程的当前理解。最后，我们指出这些新的见解如何为靶向相分离和 SG 动力学的治疗策略开辟新途径，以逆转病理性蛋白聚集并防止毒性。
