Key challenges faced by all cells include how to spatiotemporally organize complex biochemistry and how to respond to environmental fluctuations. The budding yeast Saccharomyces cerevisiae harnesses alternative protein folding mediated by yeast prion domains (PrDs) for rapid evolution of new traits in response to environmental stress. Increasingly, it is appreciated that low complexity domains similar in amino acid composition to yeast PrDs (prion-like domains; PrLDs) found in metazoa have a prominent role in subcellular cytoplasmic organization, especially in relation to RNA homeostasis. In this review, we highlight recent advances in our understanding of the role of prions in enabling rapid adaptation to environmental stress in yeast. We also present the complete list of human proteins with PrLDs and discuss the prevalence of the PrLD in nucleic-acid binding proteins that are often connected to neurodegenerative disease, including: ataxin 1, ataxin 2, FUS, TDP-43, TAF15, EWSR1, hnRNPA1, and hnRNPA2. Recent paradigm-shifting advances establish that PrLDs undergo phase transitions to liquid states, which contribute to the structure and biophysics of diverse membraneless organelles. This structural functionality of PrLDs, however, simultaneously increases their propensity for deleterious protein-misfolding events that drive neurodegenerative disease. We suggest that even these PrLD-misfolding events are not irreversible and can be mitigated by natural or engineered protein disaggregases, which could have important therapeutic applications. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.

Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.