Prion-Like Proteins in Phase Separation and Their Link to Disease

Abstract

Aberrant protein folding underpins many neurodegenerative diseases as well as certain myopathies and cancers. Protein misfolding can be driven by the presence of distinctive prion and prion-like regions within certain proteins. These prion and prion-like regions have also been found to drive liquid-liquid phase separation. Liquid-liquid phase separation is thought to be an important physiological process, but one that is prone to malfunction. Thus, aberrant liquid-to-solid phase transitions may drive protein aggregation and fibrillization, which could give rise to pathological inclusions. Here, we review prions and prion-like proteins, their roles in phase separation and disease, as well as potential therapeutic approaches to counter aberrant phase transitions.

Molecular determinants and modifiers of Matrin-3 toxicity, condensate dynamics, and droplet morphology

“…Despite the presence of a PrLD, TDP-43 and FUS toxicity in yeast is also independent of Hsp104 ( Jackrel et al., 2014 ; Johnson et al., 2008 ). Although TDP-43 and FUS are not known to function as yeast prions, these PrLDs are thought to be crucial in regulating their role in LLPS ( Franzmann and Alberti, 2019 ; Sprunger and Jackrel, 2021 ). Using immunoblotting, we confirmed consistent MATR3 protein expression in each of the strains ( Figure 1 D).…”

“…In some systems no differences are noted between these four mutants, although it was recently reported that in a mouse knock-in model, the F115C mutation did not elicit a disease phenotype ( van Bruggen et al., 2021 ). Impairment of phase separation is emerging as a key feature of ALS/FTD pathology, and now appears to also be crucial in governing MATR3 pathology ( Sprunger and Jackrel, 2021 ). It remains to be determined when MATR3 undergoes physiological LLPS, and which specific condensates MATR3 occupies.…”

“…The implication of multiple RNA-binding proteins (RBPs) in ALS/FTD, including TDP-43 ( Neumann et al., 2006 ), FUS ( Kwiatkowski et al., 2009 ; Vance et al., 2009 ), hnRNPA1 ( Kim et al., 2013 ), hnRNPA2B1 ( Kim et al., 2013 ), EWSR1 ( Couthouis et al., 2012 ; Neumann et al., 2011 ), TAF15 ( Couthouis et al., 2011 ; Neumann et al., 2011 ), ATXN2 ( Elden et al., 2010 ), and MATR3 ( Johnson et al., 2014 ), suggests that RNA dysregulation is a key mechanism underpinning ALS/FTD pathogenesis ( King et al., 2012 ). These RBPs are also characterized by the presence of large intrinsically disordered regions (IDRs) which can drive liquid-liquid phase separation (LLPS) ( Franzmann and Alberti, 2019 ; Sprunger and Jackrel, 2021 ). Because of their disordered nature and their accumulation at high concentrations upon LLPS, these RBPs are prone to misfold and aggregate, and accumulations of misfolded RBPs are the pathological hallmark of ALS/FTD ( Ling et al., 2013 ; Taylor et al., 2016 ).…”

Identification of a Region in the Common Amino-terminal Domain of Hendra Virus P, V, and W Proteins Responsible for Phase Transition and Amyloid Formation

“…With the goal of generating a rationally designed, non-amyloidogenic variant of PNT3, we carried out a bioinformatic analysis. Taking into account the ability of prion-like domains (PLDs) (i.e., IDRs enriched in Asn and Gln residues) to drive fibrillation [38,41,[95][96][97][98], we first analyzed the PNT3 sequence using various PLD predictors including LPS, PAPA, PLAAC, and PrionW (see [99] and references therein cited). No PLD was found within the PNT3 sequence, indicating that the sequence determinants that drive the fibrillation of PNT3 are distinct from those of typical PLDs.…”

Regulation of major bacterial survival strategies by transcript sequestration in a membraneless organelle

“…The resulting aberrant insoluble structures are formed due to cellular stress, impairments in protein quality control, ageing-related loss of homeostasis or mutations and repeat-expansion disorders. These structures are often toxic to the cell and may lead to severe diseases (21)(22)(23)(24). Although condensates formed by LLPS are high-order assemblies, they are still in a liquid state, whereas their misfolded structures, such as amyloids, prions, fibrilar structures and various other polymers and aggregates, have biophysical properties of gel-like or solid-like aggregates.…”