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

Research output: Contribution to journalArticle

Anny Devoy, Bernadett Kalmar, Michelle Stewart, Heesoon Park, Beverley Burke, Suzanna J Noy, Yushi Redhead, Jack Humphrey, Kitty Lo, Julian Jaeger, Alan Mejia Maza, Prasanth Sivakumar, Cinzia Bertolin, Gianni Soraru, Vincent Plagnol, Linda Greensmith, Abraham Acevedo Arozena, Adrian M Isaacs, Benjamin Davies, Pietro Fratta & 1 more Elizabeth M C Fisher

Original languageEnglish
Pages (from-to)2797-2805
Number of pages9
JournalBrain : a journal of neurology
Volume140
Issue number11
DOIs
Published1 Nov 2017

Bibliographical note

© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

King's Authors

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.

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