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Role and therapeutic potential of liquid-liquid phase separation in amyotrophic lateral sclerosis.
Journal of Molecular Cell Biology ( IF 5.3 ) Pub Date : 2021-04-10 , DOI: 10.1093/jmcb/mjaa049
Donya Pakravan 1, 2 , Gabriele Orlando 3 , Valérie Bercier 1, 2 , Ludo Van Den Bosch 1, 2
Affiliation  

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease selectively affecting motor neurons, leading to progressive paralysis. Although most cases are sporadic, ∼10% are familial. Similar proteins are found in aggregates in sporadic and familial ALS, and over the last decade, research has been focused on the underlying nature of this common pathology. Notably, TDP-43 inclusions are found in almost all ALS patients, while FUS inclusions have been reported in some familial ALS patients. Both TDP-43 and FUS possess 'low-complexity domains' (LCDs) and are considered as 'intrinsically disordered proteins', which form liquid droplets in vitro due to the weak interactions caused by the LCDs. Dysfunctional 'liquid-liquid phase separation' (LLPS) emerged as a new mechanism linking ALS-related proteins to pathogenesis. Here, we review the current state of knowledge on ALS-related gene products associated with a proteinopathy and discuss their status as LLPS proteins. In addition, we highlight the therapeutic potential of targeting LLPS for treating ALS.

中文翻译:

液-液相分离在肌萎缩侧索硬化症中的作用和治疗潜力。

肌萎缩侧索硬化症 (ALS) 是一种迟发性神经退行性疾病,选择性地影响运动神经元,导致进行性瘫痪。尽管大多数病例是散发的,但约 10% 是家族性的。在散发性和家族性 ALS 的聚集体中发现了类似的蛋白质,在过去十年中,研究一直集中在这种常见病理学的潜在性质上。值得注意的是,几乎所有 ALS 患者都发现了 TDP-43 包涵体,而在一些家族性 ALS 患者中报告了 FUS 包涵体。TDP-43 和 FUS 都具有“低复杂度结构域”(LCD),被认为是“内在无序的蛋白质”,由于 LCD 引起的弱相互作用,它们在体外形成液滴。功能失调的“液-液相分离” (LLPS)作为一种将 ALS 相关蛋白与发病机制联系起来的新机制而出现。在这里,我们回顾了与蛋白质病相关的 ALS 相关基因产物的当前知识状态,并讨论了它们作为 LLPS 蛋白的状态。此外,我们强调了靶向 LLPS 治疗 ALS 的治疗潜力。
更新日期:2020-09-25
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