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

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Devoy, Anny
Kalmar, Bernadett
Stewart, Michelle
Park, Heesoon
Burke, Beverley
Noy, Suzanna J
Redhead, Yushi
Humphrey, Jack
Lo, Kitty
Jaeger, Julian
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Oxford University Press (OUP)
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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.
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.
Palabras clave
mouse, ALS, Delta14, FUS, humanization