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Abstract
SummaryAmyotrophic 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 humanized knockin mouse models, by replacing the mouse genomic region of Sod1, Tardbp (TDP-43), and Fus, with their human orthologs, preserving human protein biochemistry and splicing with exons and introns intact. We establish a new standard of large knockin 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 humanized animals only express human protein at endogenous levels. Characterization of humanized FUS animals showed that they are phenotypically normal throughout their lifespan. These humanized 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a relentless and devastating neurodegenerative disease that causes the progressive death of motor neurons, resulting in spreading paralysis and death typically within 5 years from diagnosis (Brown and Al-Chalabi, 2017; Hardiman et al, 2017)
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 establish a new standard of large knockin allele quality control, demonstrating the utility of indirect capture for enrichment of a genomic region of interest followed by Oxford Nanopore sequencing
Summary
Amyotrophic lateral sclerosis (ALS) is a relentless and devastating neurodegenerative disease that causes the progressive death of motor neurons, resulting in spreading paralysis and death typically within 5 years from diagnosis (Brown and Al-Chalabi, 2017; Hardiman et al, 2017). ALS and frontotemporal dementia (FTD) lie on a disease spectrum with overlapping genetics, pathology, and symptoms (Abramzon et al, 2020). ALS/FTD remains incurable and essentially untreatable, with two FDA approved ALS treatments that only confer, on average, a few more months of life (Brown and Al-Chalabi, 2017; Hardiman et al, 2017). The majority of ALS is sporadic (sALS), of predominantly unknown cause, but 10% is familial (fALS), usually with an autosomal dominant mode of inheritance, with at least 30 possible monogenic forms described in several genes with varying functions
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