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

Authors
Georgia Price, Graciana de Azambuja, Chloe Williams, David Thompson, Charlotte Tibbit, Zeinab Ali, Adele Austin, Mhoriam Ahmed, Andrew Tosolini, Anny Devoy, Gemma F Codner, Lydia Teboul, Linda Greensmith, Giampietro Schiavo, Sandrine da Cruz, Elizabeth MC Fisher, Thomas J Cunningham


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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. AlthoughFUSmutations 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-targetedFUSmouse 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-inhFUSP525Lmice 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 betweenhFUSP525LandhFUSQ519Ifsexpressing mice.hFUSQ519Ifsexpressing 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 humanFUSgene and protein in ALS.

Keywords/Topics
motor neuron degeneration; humanised knock-inhfusp525lmice; mice hfusq519ifsexpressing mice; fully humanised knock-in mice; grip strength; mice; early mitochondrial gene dysregulation; amyotrophic lateral sclerosis; mutations; sarcoma fus gene

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.researchsquare.com/article/rs-9043045/latest

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