Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice
Overview
- Mary Lyon Centre at MRC Harwell
- KU Leuven
- Umeå University
- UCL Queen Square Institute of Neurology, UCL
- King’s College London
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with mutations in the Fused in Sarcoma (FUS) gene accounting for some of the most aggressive forms of the disease. Although FUS mutations are rare, accounting for only around 5% of all familial ALS cases, they are an important paradigm for study because FUS is an RNA binding protein and disruption to RNA metabolism is prominent across ALS subtypes. Here we present two novel, genomically humanised gene-targeted FUS mouse models expressing ALS patient mutations P525L or Q519Ifs. These humanised models express only human FUS protein under physiological control of the endogenous mouse promoter. Humanised knock-in hFUSP525L mice developed a mid-life onset reduction in motor performance with neuromuscular denervation, motor neuron loss, and unilateral limb muscle weakness. Pre-symptomatic transcriptomic changes suggested metabolic impairments as an early phenotype in skeletal muscle. We also directly compared phenotypes between hFUSP525L and hFUSQ519Ifs expressing mice. hFUSQ519Ifs expressing mice were more severely affected, including a pronounced developmental phenotype which varied in severity on different genetic backgrounds. The phenotypes of these new FUS-ALS models highlight the potential of fully humanised knock-in mice to aid in unravelling early disease mechanisms, and ultimately to assist in the development of therapies targeted towards the human FUS gene and protein in ALS.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Datasets cited
- bioproject:PRJNA1362973, at NCBI BioProject; found in “Data Availability”
Data Availability
RNAseq fastq files have been deposited to the NCBI Sequence Read Archive (SRA): https://
Raw data is available in Supplementary Data File 2.
Additional information is available upon request.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 30 September 2026: the first record
Recorded: type, journal, dates, 17 authors, 6 keywords, 2 funders, 125 references.
Cite
This paper
Price, G., de Azambuja, G., Williams, C., Thompson, D., Tibbit, C., Ali, Z., Austin, A., Ahmed, M., Tosolini, A., Devoy, A., Codner, G. F., Teboul, L., Greensmith, L., Schiavo, G., da Cruz, S., Fisher, E. M., & Cunningham, T. J. (2026). Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice. Research Square (preprint). https://
BibTeX
@article{price2026early,
author = {Price, Georgia and de Azambuja, Graciana and Williams, Chloe and Thompson, David and Tibbit, Charlotte and Ali, Zeinab and Austin, Adele and Ahmed, Mhoriam and Tosolini, Andrew and Devoy, Anny and Codner, Gemma F and Teboul, Lydia and Greensmith, Linda and Schiavo, Giampietro and da Cruz, Sandrine and Fisher, Elizabeth MC and Cunningham, Thomas J},
title = {{Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice}},
journal = {Research Square (preprint)},
year = {2026},
month = mar,
publisher = {Research Square},
issn = {2693-5015},
doi = {10.21203/
url = {https://
}
RIS
TY - JOUR
AU - Price, Georgia
AU - de Azambuja, Graciana
AU - Williams, Chloe
AU - Thompson, David
AU - Tibbit, Charlotte
AU - Ali, Zeinab
AU - Austin, Adele
AU - Ahmed, Mhoriam
AU - Tosolini, Andrew
AU - Devoy, Anny
AU - Codner, Gemma F
AU - Teboul, Lydia
AU - Greensmith, Linda
AU - Schiavo, Giampietro
AU - da Cruz, Sandrine
AU - Fisher, Elizabeth MC
AU - Cunningham, Thomas J
TI - Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice
T2 - Research Square (preprint)
J2 - Res Sq
PY - 2026
DA - 2026/
SN - 2693-5015
PB - Research Square
DO - 10.21203/
UR - https://
ER -
CSL-JSON
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