Elucidating a mechanism of species-specific aggregation of canine SOD1 with a degenerative myelopathy-linked mutation

A research group led by Professor Koji Yamanaka, Lecturer Seiji Watanabe, and Graduate Student Kei Hashimoto of the Nagoya University, Research Institute of Environment Medicine, Tokai National Higher Education and Research System, has discovered the mechanism of species-specific aggregation of canine SOD1 with a degenerative myelopathy (DM)-linked mutation in collaboration with Research Fellow Hiroaki Kamishina of Gifu University and Professor Yoshiaki Furukawa of Keio University.
 In DM, the E40K mutation, in which the 40th glutamate of the SOD1 protein is replaced with lysine, is thought to cause abnormal aggregation of the SOD1 protein, resulting in damage to motor neurons in the spinal cord of dogs. On the other hand, hereditary amyotrophic lateral sclerosis (ALS), a human
neurological disease, also causes motor neuron damage due to abnormal aggregation of SOD1 protein, but the E40K mutation has no effect on human SOD1, suggesting that the aggregation of canine SOD1 caused by E40K mutation is species-specific. Therefore, this research group conducted research to elucidate the mechanism of species-specific aggregation of canine SOD1 caused by the E40K mutation, and discovered that canine SOD1 is less stable and aggregates more easily than human SOD1, because canine SOD1
intrinsically has a "gap" in the highly hydrophobic region inside the protein. By manipulating the presence or absence of this "gap," they also reproduced the species-specific aggregation of SOD1 protein caused by the E40K mutation. This indicates that the inherent vulnerability of canine SOD1 derived from the "gap" is the cause of the species-specific aggregation by the E40K mutation. The results of this research are expected to lead to the development of novel therapies for DM in the future.
This work was published online in the Journal of Biological Chemistry on May 6, 2023.


雑誌名 Journal of Biological Chemistry
論文タイトル Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy–linked E40K mutation
著者 Kei Hashimoto, Seiji Watanabe, Masato Akutsu, Norifumi Muraki, Hiroaki Kamishina, Yoshiaki Furukawa, Koji Yamanaka
DOI 10.1016/j.jbc.2023.10479


Japanese ver.