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

By T. Murakami, S. Qamar, Julie Qiaojin Lin, G. K. Schierle, E. Rees, A. Miyashita, A. R. Costa, R. Dodd, F. Chan, Claire H. Michel and 20 more. Neuron, 2015

782 citations recorded by the source corpus.

Summary The 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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/41e3843235afb4a1e69adec41c2f2add9d685523

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

In Molecular Biology

In Neurology

Citations in the corpus

Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome. (2018, positive): “Associated liquid-to-solid phase transitions are also implicated in various diseases of pathological protein aggregation (Molliex et al., 2015; Murakami et al., 2015; Patel et al., 2015; Weber and Brangwynne, 2012).”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, neutral): “With those preformed seeds in the solution, the time-dependent transition of droplets into fibers could be affected (Murakami et al., 2015).”
Spatiotemporal control of intracellular phase transitions using light-activated optoDroplets (2016, positive): “These findings echo a recent in vitro study, which showed that FUS hydrogels become irreversible after either long incubation or multiple temperature cycles (Murakami et al., 2015); similar cycle-dependent irreversibility was also seen with the ALS-related protein HNRNPA1 (Molliex et al., 2015).”
Tau protein liquid–liquid phase separation can initiate tau aggregation (2018, neutral): “For example, FUS, TDP-43, and hnRNPA1 contain “prion-like” LCDs that drive their phase separation.”
Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Both the labile-to-stable gel [15] and liquid-to-solid [14,16] transitions could explain the pathological conversion of SGs to aggregates in ALS [77], but their exact relation to both cellular SGs and aggregates remains undetermined.”
Liquid phase condensation in cell physiology and disease (2017, background): “First, FUS, hnRNPA1, and other ALS-associated RNP body proteins can form hydrogels composed of amyloidlike fibers in vitro at high concentrations and/or aged samples (37, 51, 95).”
Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules (2018, background): “SG Composition and Subcellular Distribution Are Affected in iPSC Models of ALS ALS-associated mutant versions of FUS, hnRNPA2/B1, and TIA1, as well as dipeptide repeats (DPRs) derived from an expanded GGGGCC (G4C2) repeat in C9orf72, were recently reported to affect rate and dynamics of SG formation”
Distinct stages in stress granule assembly and disassembly (2016, neutral): “DOI: 10.7554/eLife.18413.001”
FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions (2018, background): “Crucially, the magnitude of this effect ( 0.60–0.80 of control) approximated that of fALS-FUS mutations ( 0.80 of control) (Murakami et al., 2015).”
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity (2017, positive): “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).”