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

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 m... Full description

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. [Display omitted] [Display omitted] •Toxicity, not loss of function, of ALS/FTD-linked mutant FUS drives disease•Intra-axonal protein synthesis is inhibited by ALS/FTD-causing mutants in FUS•Toxicity from ALS/FTD-linked mutants in FUS induces an integrated stress response•ALS/FTD mutants in FUS reduce synaptic activity without loss of nuclear FUS Mutations in FUS are causative of ALS and frontotemporal dementia (FTD). López-Erauskin et al. show that disease-causing mutant FUS inhibits intra-axonal protein synthesis and provokes hippocampal synaptic loss and dysfunction without loss of nuclear FUS function or FUS aggregation.