Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice

Overview

1. Mary Lyon Centre at MRC Harwell, Harwell, UK
2. Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
3. VIB-KU Leuven Center for Neuroscience (CNL), Department of Neurosciences, KU Leuven, Leuven Brain Institute, Belgium
4. Department of Medical and Translational Biology, Faculty of Medicine, Umeå University, Sweden
5. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
6. UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL, London, UK
7. Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Australia
8. School of Biomedical Sciences, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, St Lucia, Australia
9. Dementia Research Institute, King’s College London, London, UK
10. Dementia Research Institute, University College London, London, UK
11. Institute of Prion Diseases, MRC Prion Unit, UCL, London, UK

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

The paper links to its data and to no code of its authors: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

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://www.ncbi.nlm.nih.gov/sra/PRJNA1362973.

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, 117 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://doi.org/10.21203/rs.3.rs-9043045/v2

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.21203/rs.3.rs-9043045/v1

Early mitochondrial gene dysregulation precedes motor neuron degeneration in genomically humanised FUS mutant mice

Journal: Research Square (preprint)

In common: NCBI BioProject PRJNA1362973, genetics / omics, other condition, mouse, 1 other category, 87 references, author Mhoriam Ahmed

[2] doi:10.1242/dmm.050200

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations.

Journal: Disease models & mechanisms

In common: genetics / omics, other condition, mouse, 12 references, 2 authors

[3] doi:10.1016/j.isci.2023.108152

FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons.

Journal: iScience

In common: other condition, cellular / molecular, 13 references

[4] doi:10.1038/s41467-025-59679-1 [code]

Single-cell RNA-sequencing reveals early mitochondrial dysfunction unique to motor neurons shared across FUS- and TARDBP-ALS.

Journal: Nature communications

In common: genetics / omics, other condition, cellular / molecular, 13 references

[5] doi:10.1101/2023.11.15.565967

Creation of de novo cryptic splicing for ALS/FTD precision medicine

Journal: bioRxiv (preprint)

In common: other condition, 3 authors

[6] doi:10.3390/ijms24043181

FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation.

Journal: International journal of molecular sciences

In common: other condition, cellular / molecular, 9 references

[7] doi:10.1093/nar/gkad774

Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo.

Journal: Nucleic acids research

In common: other condition, cellular / molecular, 9 references

[8] doi:10.3390/cells12101352

Live Cell Imaging of ATP Levels Reveals Metabolic Compartmentalization within Motoneurons and Early Metabolic Changes in <i>FUS</i> ALS Motoneurons.

Journal: Cells

In common: other condition, cellular / molecular, 8 references

[9] doi:10.1038/s41593-024-01589-4 [code]

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.

Journal: Nature neuroscience

In common: other condition, mouse, cellular / molecular, 1 reference, 2 authors

[10] doi:10.1016/j.heliyon.2023.e17065

Regulation of RNG105/caprin1 dynamics by pathogenic cytoplasmic FUS and TDP-43 in neuronal RNA granules modulates synaptic loss.

Journal: Heliyon

In common: cellular / molecular, 7 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.