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

Jone López-Erauskin, Takahiro Tadokoro, Michael W. Baughn, Brian Myers, Melissa McAlonis-Downes, Carlos Chillon-Marinas, Joshua N. Asiaban, Jonathan Artates, Anh T. Bui, Anne P. Vetto, Sandra K. Lee, Ai Vy Le, Ying Sun, Mélanie Jambeau, Jihane Boubaker, Deborah Swing, Jinsong Qiu, Geoffrey G. Hicks, Zhengyu Ouyang, Xiang-Dong FuLino Tessarollo, Shuo-Chien Ling, Philippe A. Parone, Christopher E. Shaw, Martin Marsala, Clotilde Lagier-Tourenne, Don W. Cleveland, Sandrine Da Cruz

Research output: Contribution to journalArticlepeer-review

141 Citations (Scopus)


Summary 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.
Original languageEnglish
Early online date18 Oct 2018
Publication statusE-pub ahead of print - 18 Oct 2018


  • Amyotrophic Lateral Sclerosis
  • ALS
  • Frontotemporal dementia
  • FTD
  • FUS
  • TLS
  • neurodegenerative disease
  • axonal translation
  • RNA-binding proteins
  • protein synthesis


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