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.
Highlights
For over 20 years, scientists have known that mutations within the gene encoding superoxide dismutase 1 (SOD1) enzyme cause some familial forms of the human neurodegenerative disease, Amyotrophic Lateral Sclerosis [1, 2]
This research was aimed at further investigating the cellular consequences of a mutation in dog SOD1 associated with an Amyotrophic Lateral Sclerosis (ALS)-like phenotype and examined whether similar perturbations exist when associated with the equivalent horse protein
We identified prominent cellular deficits in cells expressing dog mutant SOD1 including raised superoxide ion concentrations and altered mitochondrial morphology; as such, our work further corroborates the work of Crisp et al [19], and reveals additional functional deficits associated with the dog Degenerative Myelopathy (DM) mutation that relate closely to those detected in SOD1-associated ALS [23, 25]
Summary
For over 20 years, scientists have known that mutations within the gene encoding superoxide dismutase 1 (SOD1) enzyme cause some familial forms of the human neurodegenerative disease, Amyotrophic Lateral Sclerosis (fALS) [1, 2]. A protein’s ability to cause disease can solely rest with expression of the mutant protein (complete penetrance) or its pathogenesis can be modified by other genetic or environmental factors [6]. The dog DMassociated SOD1 E40K mutation has autosomal recessive inheritance with incomplete penetrance [3]: variants in the SP110 gene, as well as aging, are the most important risk factors for disease development [7]. This means that dog E40K mutant SOD1, and other genetic variants contribute to the DM phenotype
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