Metabolic alterations in the absence of a neuromuscular phenotype in humanized SOD1A5V mice.

Abstract

Amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1) accounts for 15-30% of familial cases and is typically autosomal dominant. How single amino acid changes in this small protein cause neurodegeneration is unknown. In North America, SOD1^A5V is the most common familial SOD1 mutation and results in an aggressive form of amyotrophic lateral sclerosis. Here, we present a novel genomically humanized mouse model of SOD1^A5V , in which the mouse Sod1 locus has been replaced by the human SOD1 gene, with intact genomic architecture of exons and introns, but bearing an A5 V mutation. In agreement with previously reported human genomic knock-in mice, the phenotype is mild; however, transcriptomic and metabolomic profiling reveal significant dysregulation of glycolysis, the tricarboxylic acid cycle, and lipid metabolism. These changes suggest an early bioenergetic imbalance that precedes neuromuscular impairment. Our findings support metabolic dysfunction as an early event in amyotrophic lateral sclerosis pathogenesis. This freely available SOD1^A5V model provides a valuable tool for studying amyotrophic lateral sclerosis progression and identifying therapeutic targets for pre-symptomatic treatment.