Format

Send to

Choose Destination
Brain. 2017 Nov 1;140(11):2797-2805. doi: 10.1093/brain/awx248.

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

Author information

1
Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
2
Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
3
The Mary Lyon Centre, MRC Harwell Institute, Harwell, Oxfordshire OX11 0RD, UK.
4
UCL Genetics Institute, Gower Street, London WC1E 6BT, UK.
5
Department of Neurosciences, Università degli Studi di Padova, 35121 Padova, Italy.
6
MRC Center for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
7
Hospital Universitario de Canarias, Fundación Canaria de Investigación Sanitaria, Tenerife, Canary Islands, Spain.
8
UK Dementia Research Institute, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
9
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

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.

KEYWORDS:

ALS; Delta14; FUS; humanization; mouse

PMID:
29053787
PMCID:
PMC5841203
DOI:
10.1093/brain/awx248
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center