肌萎缩侧索硬化
包涵体
SOD1
细胞生物学
神经退行性变
蛋白质聚集
生物
失智症
泛素
疾病
应力颗粒
蛋白质折叠
化学
神经科学
医学
痴呆
病理
生物化学
翻译(生物学)
大肠杆菌
信使核糖核酸
基因
作者
Kohsuke Kanekura,Masahiko Kuroda
标识
DOI:10.1038/s41374-022-00791-x
摘要
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.
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