Department of Molecular Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, 160-8402, Japan.
Lab Invest. 2022 Sep;102(9):912-918. doi: 10.1038/s41374-022-00791-x. Epub 2022 Apr 22.
One of the critical definitions of neurodegenerative diseases is the formation of insoluble intracellular inclusion body. These inclusions are found in various neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, Parkinson's disease, and frontotemporal dementia (FTD). Each inclusion body contains disease-specific proteins and is also resistant to common detergent treatments. These aggregates are generally ubiquitinated and thus recognized as misfolded by the organism. They are observed in residual neurons at the affected sites in each disease, suggesting a contribution to disease pathogenesis. The molecular mechanisms for the formation of these inclusion bodies remain unclear. Some proteins, such as superoxide dismutase 1 (SOD1) mutant that causes familial ALS, are highly aggregative due to altered folding caused by point mutations. Still, the aggregates observed in neurodegenerative diseases contain wild-type proteins. In recent years, it has been reported that the proteins responsible for neurodegenerative diseases undergo liquid-liquid phase separation (LLPS). In particular, the ALS/FTD causative proteins such as TAR DNA-binding protein 43 kDa (TDP-43) and fused-in-sarcoma (FUS) undergo LLPS. LLPS increases the local concentration of these proteins, and these proteins eventually change their phase from liquid to solid (liquid-solid phase transition) due to abnormal folding during repetitive separation cycles into two phases and recovery to one phase. In addition to the inclusion body formation, sequestration of essential proteins into the LLPS droplets or changes in the LLPS status can directly impair neural functions and cause diseases. In this review, we will discuss the relationship between the LLPS observed in ALS causative proteins and the pathogenesis of the disease and outline potential therapeutic approaches.
神经退行性疾病的一个关键定义是形成不溶性细胞内包涵体。这些包涵体存在于各种神经退行性疾病中，如阿尔茨海默病、肌萎缩侧索硬化症 (ALS)、亨廷顿病、帕金森病和额颞叶痴呆 (FTD)。每个包涵体包含疾病特异性蛋白质，并且还能抵抗常见的去污剂处理。这些聚集体通常被泛素化，因此被机体识别为错误折叠。它们在每种疾病受影响部位的残留神经元中被观察到，表明它们对疾病发病机制有贡献。这些包涵体形成的分子机制尚不清楚。一些蛋白质，如引起家族性 ALS 的超氧化物歧化酶 1 (SOD1) 突变体，由于点突变引起的折叠改变而具有高度聚集性。然而，在神经退行性疾病中观察到的聚集体包含野生型蛋白质。近年来，据报道，导致神经退行性疾病的蛋白质经历液-液相分离 (LLPS)。特别是 ALS/FTD 致病蛋白，如 TAR DNA 结合蛋白 43 kDa (TDP-43) 和融合肉瘤 (FUS)，经历 LLPS。LLPS 增加了这些蛋白质的局部浓度，并且由于在重复分离循环中进入两相和恢复到一相的过程中异常折叠，这些蛋白质最终从液相变为固相（液-固相变）。除了包涵体形成之外，必需蛋白质被隔离到 LLPS 液滴中或 LLPS 状态的变化会直接损害神经功能并导致疾病。在这篇综述中，我们将讨论在 ALS 致病蛋白中观察到的 LLPS 与疾病发病机制之间的关系，并概述潜在的治疗方法。
