期刊
BRAIN
卷 140, 期 -, 页码 2797-2805出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx248
关键词
ALS; FUS; mouse; Delta14; humanization
资金
- UK Medical Research Council (MRC)
- UK Motor Neurone Disease Association (MNDA)
- American Amyotrophic Lateral Sclerosis Association (ALSA)
- Rosetrees Trust
- MNDA
- Thierry Latran Foundation
- MRC
- Brain Research Trust
- CONCYTEC (through CIENCIACTIVA)
- UK Embassy in Peru
- European Research Council
- Wellcome Trust Core Award [090532/Z/09/Z]
- MRC/MNDA Lady Edith Wolfson Fellowship
- NIHR University College London Hospitals Biomedical Research Centre
- MRC [MR/R005184/1, MC_EX_MR/N501931/1, UKDRI-1006, MR/K018523/1, MR/M008606/1, MR/L021056/1, G0801110, G0500288, MC_UP_1502/1, MC_UP_A390_1106] Funding Source: UKRI
- Medical Research Council [1477245, G0801110, MR/L021056/1, MC_UP_1502/1, MR/K018523/1, MC_EX_MR/N501931/1, MC_UP_A390_1106, G0500288, MR/M008606/1, MR/R005184/1] Funding Source: researchfish
- Motor Neurone Disease Association [Fisher/Apr14/874-792, Fratta/Jan15/946-795] Funding Source: researchfish
- Rosetrees Trust [M438-F1, M599, M438] Funding Source: researchfish
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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