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

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

  2. Author Address

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA.Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA.Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA.NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA.Univ Manitoba, Regenerat Med Program, Winnipeg, MB R3T 2N2, Canada.Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3T 2N2, Canada.Kings Coll London, Inst Psychiat Psychol & Neurosci, Maurice Wohl Clin Neurosci Inst, United Kingdom Dementia Res Inst Ctr, London SE5 9NU, England.Univ Auckland, Ctr Brain Res, Auckland, New Zealand.Natl Univ Singapore, Dept Physiol, Singapore 117549, Singapore.Duke NUS Grad Med Sch, Program Neurosci & Behav Disorders, Singapore, Singapore.Fate Therapeut, 3535 Gen Atom Court, San Diego, CA USA.Harvard Med Sch, Massachusetts Gen Hosp, Dept Neurol, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA.
    1. Year: 2018
    2. Date: NOV 21
    3. Epub Date: 2018 10 17
  2. Journal: Neuron
  3. CELL PRESS,
    1. 100
    2. 4
    3. Pages: 816-+
  5. Type of Article: Article
  6. ISSN: 0896-6273
  1. Abstract:

    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 fronto-temporal 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 FUSbound pre-mRNAs.

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  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1016/j.neuron.2018.09.044
  3. PMID: 30344044
  4. View record in Web of Science®
  5. WOS: 000450736600010

Library Notes

  1. Fiscal Year: FY2018-2019
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