| Streszczenie: | <p>Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition, with mutations in the Fused in Sarcoma (FUS) gene accounting for particularly severe, early onset forms of the disease. Despite extensive research into ALS, there is still no cure, and almost nothing in the way of efficacious treatments. This may be in part due to a lack of physiologically relevant models. Mouse models of ALS, and other neurodegenerative diseases, have historically been transgenic and as such, the phenotypes they display may represent artefacts of overexpression, rather than disease relevant mechanisms. </p>
<p>In this thesis I will present data characterising genomically humanised knock-in mouse models of FUS-ALS. In these knock-in mice, the mouse Fus gene has been replaced with the human FUS sequence at the endogenous mouse Fus locus. The humanised knock-in FUS mice express the human FUS gene, from the ATG start codon through to the 3’UTR and including all introns and exons, in a physiologically relevant pattern of expression. Initial characterisation of humanised FUS wildtype knock-in mice reveals minimal disruption of molecular, cellular, and overt phenotypes resulting from humanising FUS. Heterozygous humanised FUS-ALS mice show disease-relevant phenotypes, including progressive late-onset reduction in muscle strength from one year, hyperactivity and metabolic impairments. This is alongside cellular and molecular changes from 4 months, as shown by RNA sequencing data from the spinal cord and tibialis anterior muscle, and primary motor neuron culture studies. Two distinct FUS mutations are then compared to try and understand what drives different disease severity seen in FUS-ALS patients. </p>
<p>The phenotypes displayed by the FUS-ALS models highlight the potential of fully humanised knock-in mice to aid in unravelling early disease mechanisms, and ultimately produce therapies targeted towards the human gene and protein, in the context of, but not limited to, ALS.</p>
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