Stress granules in neurodegeneration – lessons learnt fromTAR DNA binding protein of 43 kDa and fused in sarcoma

摘要

Stress granules (SGs) are cytoplasmic foci that rapidly form when cells areexposed to stress. They transiently store mRNAs encoding house-keepingproteins and allow the selective translation of stress-response proteins (e.g.heat shock proteins). Besides mRNA, SGs contain RNA-binding proteins,such as T cell internal antigen-1 and poly(A)-binding protein 1, which canserve as characteristic SG marker proteins. Recently, some of these SGmarker proteins were found to label pathological TAR DNA binding proteinof 43 kDa (TDP-43)- or fused in sarcoma (FUS)-positive cytoplasmicinclusions in patients with amyotrophic lateral sclerosis and frontotemporallobar degeneration. In addition, protein aggregates in other neurodegenerativediseases (e.g. tau inclusions in Alzheimer’s disease) show a co-localizationwith T cell internal antigen-1 as well. Moreover, several RNA-bindingproteins that are commonly found in SGs have been genetically linked toneurodegeneration. This suggests that SGs might play an important role inthe pathogenesis of these proteinopathies, either by acting as a seed forpathological inclusions, by mediating translational repression or by trappingessential RNA-binding proteins, or by a combination of these mechanisms.This minireview gives an overview of the general biology of SGsand highlights the recently identified connection of SGs with TDP-43, FUSand other proteins involved in neurodegenerative diseases. We propose thatpathological inclusions containing RNA-binding proteins, such as TDP-43and FUS, might arise from SGs and discuss how SGs might contribute toneurodegeneration via toxic gain or loss-of-function mechanisms.