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Clinical, histopathological, and biochemical characterization of the canine model of SOD1-mediated amyotrophic lateral sclerosis

  • P3-310
  • 小畠 結 / Yui Kobatake:1 小宅 香苗 / Kanae Oyake:2 津久井 利広 / Toshihiro Tsukui:3 酒井 洋樹 / Hiroki Sakai:1,2 大和 修 / Osamu Yamato:4 齋藤 弥代子 / Miyoko Saito:5 漆谷 真 / Makoto Urushitani:6 加藤 信介 / Shinsuke Kato:7 佐々木 淳 / Jun Sasaki:8 柴田 早苗 / Sanae Shibata:1,2 前田 貞俊 / Sadatoshi Maeda:1,2 神志那 弘明 / Hiroaki Kamishina:1,2 
  • 1:岐阜大学大学院連合獣医学研究科 / The United Graduate School of Veterinary Sciences Gifu Univ, Gifu, Japan  2:岐阜大学応用生物科学部 / Faculty of Applied Biological Sciences Gifu Univ, Gifu, Japan 3:日本全薬工業株式会社 / Nippon Zenyaku Kogyo Co. Ltd., Fukushima, Japan 4:鹿児島大学共同獣医学部 / Joint Faculty of Veterinary Medicine Kagoshima Univ, Kagoshima, Japan 5:麻布大学獣医学部 / School of Veterinary Medicine, Azabu Univ, Kanagawa, Japan 6:京都大学大学院医学研究科 / Graduate School of Medicine Kyoto Univ, Kyoto, Japan 7:鳥取大学医学部 / Tottori Univ Faculty of Medicine, Tottori, Japan 8:岩手大学農学部 / Faculty of Agriculture Iwate Univ, Iwate, Japan 

Amyotrophic lateral sclerosis (ALS) is a motor neuron-specific neurodegenerative disorder. Superoxide dismutase 1 (SOD1) gene mutations have been known to cause approximately 20% of familial ALS cases. In dogs, SOD1 mutations (E40K and T18S) have been linked to degenerative myelopathy (DM). In the present study, we described a detailed clinical course of DM, histopathological characteristics of affected spinal cords, and biochemical properties of E40K proteins to provide a better understanding of this novel canine model of ALS.
The clinical symptoms in dogs were characterized by a late-onset, progressive and fatal spinal cord disorder. The early signs were pelvic general proprioceptive ataxia and upper motor neuron paraparesis. The clinical signs progressed to lower motor neuron quadriplegia, and eventually respiratory failure. The histopathological features of postmortem spinal tissues were axonal loss and demyelination. Immunohistochemistry with an E40K-specific antibody revealed accumulation of mutant SOD1 species in neuronal cell bodies. Biochemical analyses of E40K proteins demonstrated their reduced detergent solubility and tendency to form high molecular weight complexes.
A variety of treatments have been found effective in transgenic mice expressing human mutant SOD1, but few treatments have proven successful in clinical trials. Rodent ALS models are likely to possess very high levels of mutant SOD1 expression, which may induce pathologic processes distinct from those affecting ALS patients. Dogs with DM, on the other hand, result from a spontaneous SOD1 mutation and may mirror more closely human ALS.

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