Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease

Abstract

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.

Keywords: ALS; Disaggregase; Phase transition; Prion; Prion-like domains; RNA-binding proteins.

Fig. 1

Associations between human PrLD-containing proteins and the Gene Ontology categories enriched for them. Columns correspond to the nine GO Slim categories enriched for human PrLD-containing proteins (Table 1), and rows correspond to the PrLD-containing proteins; the cell indexed by a given row and column is colored blue if the corresponding protein is annotated as belonging to the corresponding category, and gray otherwise. The rows and columns are hierarchically clustered based on correlation of GO Slim annotations. The PLAAC COREscore is also indicated in the far right column using a red color gradient with ranging from black (score 0) to saturated red (score 64), as indicated by the color bar. Rows and columns are ordered by a correlation-based clustering. The 66 of 240 PrLD-containing proteins not associated with any of these categories are not shown (the full list of human proteins with PrLDs is presented in Table S1).

Fig. 2

Phase transitions of prion-like domains. RNA-binding proteins (RNA recognition motif depicted by purple circles) can reversibly coalesce into dynamic liquid droplets through transient interactions in their prion-like domains (PrLDs depicted as purple lines). Droplet persistence over time, or mutations in PrLDs that introduce potent steric zippers, can drive further condensation of aged droplets into a less dynamic form that can give rise to solid fibrillar protein aggregates that accrue in neurodegenerative disease.