Species‐specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1)

Abstract

A glutamic acid to lysine (E40K) residue substitution in superoxide dismutase 1 (SOD1) is associated with canine degenerative myelopathy: the only naturally occurring large animal model of amyotrophic lateral sclerosis (ALS). The E40 residue is highly conserved across mammals, except the horse, which naturally carries the (dog mutant) K40 residue. Here we hypothesized that in vitro expression of mutant dog SOD1 would recapitulate features of human ALS (ie, SOD1 protein aggregation, reduced cell viability, perturbations in mitochondrial morphology and membrane potential, reduced ATP production, and increased superoxide ion levels); further, we hypothesized that an equivalent equine SOD1 variant would share similar perturbations in vitro, thereby explain horses' susceptibility to certain neurodegenerative diseases. As in human ALS, expression of mutant dog SOD1 was associated with statistically significant increased aggregate formation, raised superoxide levels (ROS), and altered mitochondrial morphology (increased branching (form factor)), when compared to wild-type dog SOD1-expressing cells. Similar deficits were not detected in cells expressing the equivalent horse SOD1 variant. Our data helps explain the ALS-associated cellular phenotype of dogs expressing the mutant SOD1 protein and reveals that species-specific sequence conservation does not necessarily predict pathogenicity. The work improves understanding of the etiopathogenesis of canine degenerative myelopathy.

Honokiol alleviated neurodegeneration by reducing oxidative stress and improving mitochondrial function in mutant SOD1 cellular and mouse models of amyotrophic lateral sclerosis

“…The mitochondrial morphology abnormalities and mitochondrial function disruption is a common pathology appeared in ALS patients and ALS models. The impaired MMP, ATP production and mitochondrial respiratory chain complex were reported in ALS patients and ALS models 85 , 86 . The decrease of mitochondrial biogenesis and mitophagy, and elevation of mitochondrial fission level were observed in the peripheral blood mononuclear cells from the ALS patients 24 .…”

Molecular Mechanisms of Aggregation of Canine SOD1 E40K Amyloidogenic Mutant Protein

“…The E40 residue is highly conserved in mammals, except horses, donkeys, and armadillos [37]. Mutation at E40 cause DM in dogs, but DM has not been reported in horses.…”