ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

Abstract

SummaryThe mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…By analogy to hnRNPA1 (Molliex et al , 2015)‐, TDP‐43 (Conicella et al , 2016)‐, FUS (Murakami et al , 2015)‐, and C9orf72‐derived dipeptide repeats (Lee et al , 2016), tau LLPS could act to initiate tau aggregation in AD and FTD. We suggest that protein LLPS may be a biophysical mechanism underlying multiple protein aggregation and neurodegenerative diseases.…”

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

“…We recently showed that FUS LC maintains its primarily disordered structure within in vitro models of RNP granules (Burke et al , 2015). However, the high local concentration of proteins in RNP granules formed by LLPS may potentiate the conversion of liquid compartments into solid cytoplasmic aggregates and inclusions observed in disease (Murakami et al , 2015; Patel et al , 2015). This phenomenon may be enhanced by mutations in disease‐associated ribonuclear proteins that increase their cytoplasmic concentration (Vance et al , 2013) or aggregation propensity (Kim et al , 2013).…”

Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis

“…In the pathological process, the LC domains of the N terminus of TLS drives its phase transitions, reversibly shifting between dispersed, liquid droplet, and hydrogel-like phases [31,38,53]. The mutation of TLS severely limits this ability to repeatedly shift between these phases.…”

“…Actually, the mutated TLSs induce the propensity of TLS to condense into poorly soluble, stable, fibrillary hydrogel-like assemblies. These stably irreversible TLS aggregates, which selectively capture other RNA-binding proteins, impair local RNA-binding protein granule functions, and attenuate novel protein syntheses in the axon terminals of cultured neurons [31]. Modulation of these protein phase transitions might be a possible therapeutic target.…”

“…Aggregation or precipitation of proteins is recently emerging as a central concerns regarding various disorders related to neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) [1,2,8,[30][31][32][33]. It has been well recognized that precipitation of proteins in living cells causes disturbance of biological processes and gives rise to neurodegenerative diseases in the neurons.…”