Localization of a mutant SOD1 protein in E40K-heterozygous dogs: Implications for non-cell-autonomous pathogenesis of degenerative myelopathy.

Abstract

Canine degenerative myelopathy (DM) is a fatal neurodegenerative disorder. Dogs with typical clinical signs carry homozygous mutations in the superoxide dismutase 1 (SOD1) gene; therefore, DM is regarded as a naturally-occurring model of amyotrophic lateral sclerosis (ALS). Despite the presence of a toxic mutant protein, E40K-SOD1 heterozygotes rarely develop clinical signs. Therefore, E40K-heterozygotes may provide insights into the subclinical and early phase of mutant SOD1-related pathology. In order to identify the distribution of mutant SOD1 in the spinal cords of E40K-heterozygotes, we developed a monoclonal antibody 16G9 that reacts to the mutant E40K-SOD1 protein. We found that the spinal cords of E40K-heterozygotes display white matter degeneration, the severity of which was markedly less than that in E40K-homozygotes. In E40K-heterozygotes, 16G9-reactive SOD1 accumulated predominantly in reactive astrocytes, while spinal neurons remained almost completely free of this form of SOD1 proteins. In contrast, all symptomatic E40K-homozygotes contained 16G9-reactive SOD1 in their spinal neurons and reactive astrocytes. These results suggest that mutant SOD1 proteins accumulate in reactive astrocytes during the early phase of DM pathology, which may contribute to subclinical neurodegeneration. The early involvement of reactive astrocytes in the pathogenesis of DM is strongly suspected and warrants further investigations in the context of non-cell autonomous neuronal death, as proposed for ALS.

• Authors: Yui Kobatake, Hiroki Sakai, Toshihiro Tsukui, Osamu Yamato, Moeko Kohyama, Jun Sasaki, Shinsuke Kato, Makoto Urushitani, Sadatoshi Maeda, Hiroaki Kamishina
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 372 Pg. 369-378 (Jan 15 2017) ISSN: 1878-5883 [Electronic] Netherlands
• PMID: 27838005 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• AIF1 protein, human
• Antibodies
• Calcium-Binding Proteins
• DNA-Binding Proteins
• Glial Fibrillary Acidic Protein
• Microfilament Proteins
• Glutamic Acid
• Superoxide Dismutase-1
• Lysine

Topics

• Amyotrophic Lateral Sclerosis (genetics, pathology, veterinary)
• Animals
• Antibodies (metabolism)
• Calcium-Binding Proteins
• DNA-Binding Proteins (metabolism)
• Disease Models, Animal
• Dogs
• Gene Expression Regulation (genetics)
• Glial Fibrillary Acidic Protein (metabolism)
• Glutamic Acid (genetics)
• HEK293 Cells
• Humans
• Immunoprecipitation
• Lysine (genetics)
• Microfilament Proteins
• Mutation (genetics)
• Spinal Cord (metabolism)
• Superoxide Dismutase-1 (genetics, immunology)
• Transfection