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

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…

• WT
  Wellcome Trust
• AS
  Alzheimer Society
• EC
  European Commission

  Awards: FP/2007-2013, 322817, 2007-2013, FP/2007-2013)/ERC
• NI
  National Institutes of Health

  Award: FP/2007-2013
• CI
  Canadian Institutes of Health Research
• MR
  Medical Research Council

  Awards: MR/K02292X/1, MC_G1000734
• EA
  Engineering and Physical Sciences Research Council

  Awards: EP/H018301/1, FP/2007-2013