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

Draper, A C E; Wilson, Z; Maile, C A; Faccenda, D; Campanella, M; Piercy, R J


A C E Draper

Z Wilson

C A Maile

D Faccenda

M Campanella

R J Piercy


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.


Draper, A. C. E., Wilson, Z., Maile, C. A., Faccenda, D., Campanella, M., & Piercy, R. J. (2019). Species-specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1). FASEB Journal,

Journal Article Type Article
Acceptance Date Oct 8, 2019
Publication Date Nov 25, 2019
Deposit Date Nov 30, 2019
Publicly Available Date Nov 26, 2020
Print ISSN 0892-6638
Publisher Federation of American Society of Experimental Biology (FASEB)
Peer Reviewed Peer Reviewed
Public URL


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