Publicación:
Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice

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dc.contributor.author Devoy, Anny es_PE
dc.contributor.author Kalmar, Bernadett es_PE
dc.contributor.author Stewart, Michelle es_PE
dc.contributor.author Park, Heesoon es_PE
dc.contributor.author Burke, Beverley es_PE
dc.contributor.author Noy, Suzanna J es_PE
dc.contributor.author Redhead, Yushi es_PE
dc.contributor.author Humphrey, Jack es_PE
dc.contributor.author Lo, Kitty es_PE
dc.contributor.author Jaeger, Julian es_PE
dc.contributor.author Mejia Maza, Alan es_PE
dc.contributor.author Sivakumar, Prasanth es_PE
dc.contributor.author Bertolin, Cinzia es_PE
dc.contributor.author Soraru, Gianni es_PE
dc.contributor.author Plagnol, Vincent es_PE
dc.contributor.author Greensmith, Linda es_PE
dc.contributor.author Acevedo Arozena, Abraham es_PE
dc.contributor.author Isaacs, Adrian M es_PE
dc.contributor.author Davies, Benjamin es_PE
dc.contributor.author Fratta, Pietro es_PE
dc.contributor.author Fisher, Elizabeth M C es_PE
dc.date.accessioned 2024-05-30T23:13:38Z
dc.date.available 2024-05-30T23:13:38Z
dc.date.issued 2017-10-07
dc.description A.D., H.P., B.B., J.J., A.A.A. and E.M.C.F. were funded by the UK Medical Research Council (MRC), the UK Motor Neurone Disease Association (MNDA), the American Amyotrophic Lateral Sclerosis Association (ALSA) and the Rosetrees Trust. B.K. and L.G. were supported by the MNDA and the Thierry Latran Foundation. J.H. is funded by the MRC and the Brain Research Trust. A.M.M. is supported by a PhD studentship from CONCYTEC (through CIENCIACTIVA) and the UK Embassy in Perú. P.S. is funded by the MRC. A.I. is funded by the MNDA and the European Research Council. B.D. is supported by Wellcome Trust Core Award Grant Number 090532/Z/09/Z. P.F. is supported by a MRC/MNDA Lady Edith Wolfson Fellowship, the Rosetrees Trust and NIHR University College London Hospitals Biomedical Research Centre.
dc.description.abstract Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease-with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.
dc.description.sponsorship Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica - Concytec
dc.identifier.doi https://doi.org/10.1093/brain/awx248
dc.identifier.scopus 2-s2.0-85032967885
dc.identifier.uri https://hdl.handle.net/20.500.12390/1337
dc.language.iso eng
dc.publisher Oxford University Press (OUP)
dc.relation.ispartof Brain
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.subject mouse
dc.subject ALS es_PE
dc.subject Delta14 es_PE
dc.subject FUS es_PE
dc.subject humanization es_PE
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.00.00
dc.title Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice
dc.type info:eu-repo/semantics/article
dspace.entity.type Publication
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