Lu Xingyu, Lu Jiongtong, Li Shengnan, Feng Sifan, Wang Yan, Cui Lili
Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
The Marine Biomedical Research Institute of Guangdong, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang, Guangdong, China.
Aging Dis. 2024 Apr 20;16(2):769-786. doi: 10.14336/AD.2024.0209.
It is widely accepted that living organisms form highly dynamic membrane-less organelles (MLOS) with various functions through phase separation, and the indispensable role that phase separation plays in the mechanisms of normal physiological functions and pathogenesis is gradually becoming clearer. Pathological aggregates, regarded as hallmarks of neurodegenerative diseases, have been revealed to be closely related to aberrant phase separation. Specific proteins are assembled into condensates and transform into insoluble inclusions through aberrant phase separation, contributing to the development of diseases. In this review, we present an overview of the progress of phase separation research, involving its biological mechanisms and the status of research in neurodegenerative diseases, focusing on five main disease-specific proteins, tau, TDP-43, FUS, α-Syn and HTT, and how exactly these proteins reside within dynamic liquid-like compartments and thus turn into solid deposits. Further studies will yield new perspectives for understanding the aggregation mechanisms and potential therapeutic strategies, and future research directions are anticipated.
人们普遍认为，活生物体通过相分离形成具有各种功能的高度动态的无膜细胞器（MLOS），并且相分离在正常生理功能和发病机制中所起的不可或缺的作用正逐渐变得清晰。病理聚集体被视为神经退行性疾病的标志，已被揭示与异常相分离密切相关。特定蛋白质通过异常相分离组装成凝聚物并转化为不溶性内含物，从而导致疾病的发展。在这篇综述中，我们概述了相分离研究的进展，包括其生物学机制以及神经退行性疾病的研究现状，重点关注五种主要的疾病特异性蛋白质，即tau、TDP-43、FUS、α-突触核蛋白和亨廷顿蛋白（HTT），以及这些蛋白质究竟如何存在于动态的类液体隔室中并进而变成固体沉积物。进一步的研究将为理解聚集机制和潜在治疗策略带来新的视角，并预期未来的研究方向。
