In vitro evidence of propagation of superoxide dismutase-1 protein aggregation in canine degenerative myelopathy

N Tanaka; S Kimura; Y O Kamatari; K Nakata; Y Kobatake; M Inden; O Yamato; M Urushitani; S Maeda; H Kamishina

doi:10.1016/j.tvjl.2021.105710

In vitro evidence of propagation of superoxide dismutase-1 protein aggregation in canine degenerative myelopathy

Vet J. 2021 Aug:274:105710. doi: 10.1016/j.tvjl.2021.105710. Epub 2021 Jun 21.

Authors

N Tanaka¹, S Kimura², Y O Kamatari³, K Nakata², Y Kobatake¹, M Inden⁴, O Yamato⁵, M Urushitani⁶, S Maeda⁷, H Kamishina⁸

Affiliations

¹ Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
² The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
³ Division of Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
⁴ Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, 1-26-4 Daigaku-Nishi, Gifu, 501-1196, Japan.
⁵ Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima, 890-8580, Japan.
⁶ Department of Neurology, Shiga Univ. of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan.
⁷ Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan.
⁸ Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan; The United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1193, Japan. Electronic address: kamicna@gifu-u.ac.jp.

PMID: 34166783
DOI: 10.1016/j.tvjl.2021.105710

Abstract

Canine degenerative myelopathy (DM) is a progressive and fatal neurodegenerative disorder that has been linked to mutations in the superoxide dismutase 1 (SOD1) gene. The accumulation of misfolded protein aggregates in spinal neurons and astrocytes is implicated as an important pathological process in DM; however, the mechanism of protein aggregate formation is largely unknown. In human neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), cell-to-cell propagation of disease-relevant proteins has been demonstrated. Therefore, in this study, propagation of aggregation-forming property of mutant SOD1 protein in DM in vitro was investigated. This study demonstrated that aggregates composed of canine wild type SOD1 protein were increased by co-transfection with canine mutant SOD1 (E40K SOD1), indicating intracellular propagation of SOD1 aggregates. Further, aggregated recombinant SOD1 proteins were released from the cells, taken up by other cells, and induced further aggregate formation of normally folded SOD1 proteins. These results suggest intercellular propagation of SOD1 aggregates. The hypothesis of cell-to-cell propagation of SOD1 aggregates proposed in this study may underly the progressive nature of DM pathology.

Keywords: Aggregates; Canine; Cell-to-cell propagation; Degenerative myelopathy; Superoxide dismutase 1.

MeSH terms

Animals
Cell Line, Tumor
Disease Models, Animal
Dog Diseases / genetics*
Dog Diseases / pathology
Dogs
Mice
Mutation
Neurodegenerative Diseases / genetics
Neurodegenerative Diseases / veterinary
Plasmids
Protein Aggregation, Pathological / veterinary*
Protein Folding
Spinal Cord Diseases / genetics
Spinal Cord Diseases / veterinary
Superoxide Dismutase-1 / chemistry
Superoxide Dismutase-1 / genetics*
Transfection

Substances

Superoxide Dismutase-1