Stress granules and neurodegeneration

神经退行性变 RNA结合蛋白 细胞生物学 应力颗粒 平动调节 神经科学 核糖核酸 PI3K/AKT/mTOR通路 失智症 肌萎缩侧索硬化 生物 信号转导 医学 疾病 遗传学 病理 痴呆 翻译(生物学) 信使核糖核酸 基因
作者
Benjamin Wolozin,Pavel Ivanov
出处
期刊:Nature Reviews Neuroscience [Springer Nature]
卷期号:20 (11): 649-666 被引量:524
标识
DOI:10.1038/s41583-019-0222-5
摘要

Recent advances suggest that the response of RNA metabolism to stress has an important role in the pathophysiology of neurodegenerative diseases, particularly amyotrophic lateral sclerosis, frontotemporal dementias and Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membraneless organelles termed stress granules (SGs). These structures form through a process of liquid–liquid phase separation. Multiple biochemical pathways regulate SG biology. The major signalling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)–eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas the pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic, persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. We suggest a model describing how intrinsic vulnerabilities within the cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and it suggests new targets for disease intervention. RNA-binding proteins regulate the use of mRNA during periods of stress, in part through the formation of transient membraneless organelles known as stress granules. In this Review, Wolozin and Ivanov examine the biology of such granules in neurons and their potential roles in a number of neurodegenerative diseases.
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