Generation and analysis of innovative genomically humanised knock-in SOD1, TARDBP (TDP-43), and FUS mouse models
2021
SUMMARY Amyotrophic lateral sclerosis / frontotemporal dementia (ALS/FTD) is a fatal neurodegenerative disorder, and continued innovation is needed for improved understanding and for developing therapeutics. We have created next-generation genomically humanised knock-in mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43) and Fus, with their human orthologues, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new-standard of large knock-in allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing. Extensive analysis shows that homozygous humanised animals only express human protein, at endogenous levels. Characterisation of humanised FUS animals showed that they are phenotypically normal throughout their lifespan. These humanised strains are vital for preclinical assessment of interventions and serve as templates for the addition of coding or non-coding human ALS/FTD mutations to dissect disease pathomechanisms, in a physiological context.
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