ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

Neuron. 2018 Nov 21;100(4):816-830.e7. doi: 10.1016/j.neuron.2018.09.044. Epub 2018 Oct 18.


Through the generation of humanized FUS mice expressing full-length human FUS, we identify that when expressed at near endogenous murine FUS levels, both wild-type and ALS-causing and frontotemporal dementia (FTD)-causing mutations complement the essential function(s) of murine FUS. Replacement of murine FUS with mutant, but not wild-type, human FUS causes stress-mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without loss of nuclear FUS or its cytoplasmic aggregation. Most strikingly, accumulation of mutant human FUS is shown to activate an integrated stress response and to inhibit local, intra-axonal protein synthesis in hippocampal neurons and sciatic nerves. Collectively, our evidence demonstrates that human ALS/FTD-linked mutations in FUS induce a gain of toxicity that includes stress-mediated suppression in intra-axonal translation, synaptic dysfunction, and progressive age-dependent motor and cognitive disease without cytoplasmic aggregation, altered nuclear localization, or aberrant splicing of FUS-bound pre-mRNAs. VIDEO ABSTRACT.

Keywords: ALS; Amyotrophic Lateral Sclerosis; FTD; FUS; Frontotemporal dementia; RNA-binding proteins; TLS; axonal translation; neurodegenerative disease; protein synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Axons / pathology
  • Axons / physiology*
  • Cells, Cultured
  • Female
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Loss of Function Mutation / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pregnancy
  • Protein Biosynthesis / physiology*
  • RNA-Binding Protein FUS / biosynthesis
  • RNA-Binding Protein FUS / genetics*


  • FUS protein, mouse
  • RNA-Binding Protein FUS