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

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

Author information

1
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
2
Department of Anesthesiology, University of California at San Diego, La Jolla, CA 92093, USA.
3
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD, 21702, USA.
4
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
5
Regenerative Medicine Program and Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, R3T 2N2, Canada.
6
United Kingdom Dementia Research Institute Centre, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 9NU London, U.K; Centre for Brain Research, University of Auckland, Auckland, New Zealand.
7
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA.
8
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: dcleveland@ucsd.edu.
9
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: sdacruz@ucsd.edu.

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 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

PMID:
30344044
DOI:
10.1016/j.neuron.2018.09.044
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