翻译后修饰介导的相分离在神经退行性疾病中的作用

The Role of Post-translational Modification Mediated Phase Separation in Neurodegenerative Diseases

近几年,生物大分子的液-液相分离(liquid-liquid phase separation, LLPS)的研究受到极大关注。相分离是指生物大分子在细胞内的一种特殊动态聚集状态,处于相分离态的生物大分子,例如蛋白质也被比作“无膜细胞器”。这类无膜细胞器介导细胞的各种生理活动和功能,对细胞的基因表达、信号传导、应激响应等有着重要的作用。在正常的生理状态下,体内相分离是动态变化且维持稳态性,一旦出现异常的相分离则预示着疾病的发生,包括神经退行性疾病、肿瘤和炎症等。神经退行性疾病是神经元和神经髓鞘功能异常或丧失进而出现认知、运动和语言障碍的一类疾病,这类疾病的发病机制主要包括基因突变、蛋白质异常聚集、氧化应激异常和线粒体功能异常等。神经退行性疾病中蛋白质异常聚集被证明是相分离现象,例如Tau(microtubule-associated protein-Tau)异常相分离诱发的阿尔茨海默病(Alzheimer’s disease, AD)、FUS(fused in sarcoma/translocated in liposarcoma)相分离诱发的肌萎缩脊髓侧索硬化症(amyotrophic lateral sclerosis, ALS)等。蛋白质的翻译后修饰(PTM)在调控细胞功能中具有重要作用,通过磷酸化、甲基化、乙酰化等修饰影响蛋白质相分离的发生和进程。本文将从蛋白质相分离的概念、相分离发生的生物化学基础以及翻译后修饰调控的相分离在神经退行性疾病的作用进行阐述。

In recent years,liquid-liquid phase separation of biological macromolecules has attracted great attention.Phase separation refers to a special state of biological macromolecules gathering in cells,and its structure is considered to be a"membrane-less organelle".Membrane-less organelles mediate multiple physiological processes and play key roles in gene expression,signal transduction,stress response and so on.Phase separation is dynamically changing and homeostatic under normal physiological state.However,abnormal phenomenon of phase separation suggests the development of diseases,such as neurodegenerative diseases,tumors,inflammation,and so on.Neurodegenerative diseases induced cognitive,motor,and language impairment,are a diverse set of disorders in which dysfunction or loss of neurons and neuronal myelin sheaths.The mechanisms of these diseases include gene mutations,abnormal protein aggregation,oxidative stress,and mitochondrial dysfunction.Overaggregation of proteins have been regarded as phase separation in neurodegenerative diseases,such as Alzheimer’s disease induced by microtubule-associated protein-Tau overaggregation,amyotrophic lateral sclerosis induced by fused in sarcoma/translocated in liposarcoma,and other related neurodegenerative diseases.Post-translational modification plays an important role in regulating the cell biological function,which,as a result,leads to aberrant phase separation through phosphorylation,methylation,acetylation and post-translational modification.This article reviews the concept of phase separation,the biochemical basis of phase separation,and particularly focusing on the role of post-translational modification mediated phase separation in neurodegenerative diseases.