The implications of physiological biomolecular condensates in amyotrophic lateral sclerosis

In recent years, there has been an emphasis on the role of phase-separated biomolecular condensates, especially stress granules, in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). This is largely due to several ALS-associated mutations occurring in genes involved in stress granule assembly and observations that pathological inclusions detected in ALS patient neurons contain stress granule proteins, including the ALS-linked proteins TDP-43 and FUS. However, protein components of stress granules are also found in numerous other phase-separated biomolecular condensates under physiological conditions which are inadequately discussed in the context of ALS. In this review, we look beyond stress granules and describe the roles of TDP-43 and FUS in physiological condensates occurring in the nucleus and neurites, such as the nucleolus, Cajal bodies, paraspeckles and neuronal RNA transport granules. We also discuss the consequences of ALS-linked mutations in TDP-43 and FUS on their ability to phase separate into these stress-independent biomolecular condensates and perform their respective functions. Importantly, biomolecular condensates sequester multiple overlapping protein and RNA components, and their dysregulation could contribute to the observed pleiotropic effects of both sporadic and familial ALS on RNA metabolism.

Automated summary

There has been increasing attention to the role of phase-separated biomolecular condensates, specifically stress granules, in neurodegenerative diseases like ALS. ALS-associated mutations in genes involved in stress granule assembly have been found, and stress granule proteins have been detected in pathological inclusions in ALS patient neurons. However, protein components of stress granules are also present in other physiological biomolecular condensates, which have not been adequately discussed in relation to ALS. This review explores the functions of TDP-43 and FUS in physiological condensates occurring in the nucleus and neurites beyond stress granules, and discusses the impact of ALS-linked mutations on their ability to phase separate and perform their functions in stress-independent biomolecular condensates.