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Home / Equine Research Bank / FASEB J / Species-specific consequences of an E40K missense mutation i...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology2019; 34(1); 458-473; doi: 10.1096/fj.201901455R

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.
© 2019 Federation of American Societies for Experimental Biology.
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Publication Date: 2019-11-25 PubMed ID: 31914665DOI: 10.1096/fj.201901455RGoogle Scholar: Lookup
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  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This study examines the effects of a specific mutation in the superoxide dismutase 1 (SOD1) gene, commonly associated with canine degenerative myelopathy. The researchers found that this mutation displays similar cellular characteristics to human ALS and suggests that it could potentially influence the disease’s progression in dogs, but not horses.

Research Objectives and Hypothesis

  • The main objective of this research was to examine the E40K mutation in the SOD1 gene, which has been associated with canine degenerative myelopathy, an animal model of amyotrophic lateral sclerosis (ALS).
  • The study hypothesized that the expression of the mutant dog SOD1 in vitro would show similar signs of human ALS, such as protein aggregation, decreased cell viability, alterations in mitochondrial morphology and membrane potential, reduced ATP production, and increased superoxide ion levels.
  • Additionally, it was hypothesized that an equivalent equine (horse) SOD1 variant would show similar perturbations, explaining the susceptibility of horses to certain neurodegenerative diseases.

Primary Findings

  • When comparing mutant dog SOD1-expressing cells to those expressing the wild-type, the researchers found a significant increase in aggregate formation and superoxide levels, as well as altered mitochondrial morphology. These are all characteristics associated with human ALS.
  • These deficits were not found in cells expressing the horse-equivalent SOD1 variant, contradicting one aspect of their hypothesis.

Significance and Conclusions

  • The results of this study help to explain the cellular phenotype associated with ALS in dogs expressing the mutant SOD1 protein.
  • The research demonstrated that the typically conserved E40 residue in the SOD1 gene does not necessarily predict pathogenic susceptibility across different species — in this case, horses.
  • The findings improve our understanding of the etiopathogenesis, or the cause and development, of canine degenerative myelopathy. This could contribute to potential future treatments or preventative measures for this disease and others like it.

Cite This Article

APA
Draper ACE, Wilson Z, Maile C, Faccenda D, Campanella M, Piercy RJ. (2019). Species-specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1). FASEB J, 34(1), 458-473. https://doi.org/10.1096/fj.201901455R

Publication

FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
NlmUniqueID: 8804484
Country: United States
Language: English
Volume: 34
Issue: 1
Pages: 458-473

Researcher Affiliations

Draper, Alexandra C E
  • Comparative Neuromuscular Disease Laboratory, Royal Veterinary College, University of London, London, UK.
Wilson, Zoe
  • Comparative Neuromuscular Disease Laboratory, Royal Veterinary College, University of London, London, UK.
Maile, Charlotte
  • Comparative Neuromuscular Disease Laboratory, Royal Veterinary College, University of London, London, UK.
Faccenda, Danilo
  • Mitochondrial Cell Biology and Pharmaceutical Research Unit, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK.
Campanella, Michelangelo
  • Mitochondrial Cell Biology and Pharmaceutical Research Unit, Department of Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK.
  • University College London Consortium for Mitochondrial Research, University College London, University of London, London, UK.
Piercy, Richard J
  • Comparative Neuromuscular Disease Laboratory, Royal Veterinary College, University of London, London, UK.

MeSH Terms

  • Adenosine Triphosphate / metabolism
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Dogs
  • Horses
  • Humans
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mutation, Missense
  • Phylogeny
  • Species Specificity
  • Superoxide Dismutase-1 / genetics
  • Transgenes / physiology

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Citations

This article has been cited 3 times.
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