May 22, 2023
Nagoya University, Tokai National Higher Education and Research System
Keio University
A joint research group, including graduate student Kei Hashimoto, Lecturer Seiji Watanabe, and Professor Koji Yamanaka from the Research Institute of Environmental Medicine at Nagoya University (part of the Tokai National Higher Education and Research System); Hiroaki Koshina, a specially appointed research fellow at the Science Research Center, Gifu University, and director of the KyotoAR Advanced Animal Medical Center; and Professor Yoshiaki Furukawa from the Faculty of Science and Technology at Keio University, has elucidated the species-specific aggregation mechanism of the SOD1 protein, which causes canine degenerative myelopathy (DM). In DM, the E40K mutation, where the 40th glutamic acid of the SOD1 protein is replaced by lysine, is thought to cause abnormal aggregation of the SOD1 protein, leading to damage to motor neurons in the spinal cord. On the other hand, in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease in humans, motor neurons are also damaged by abnormal aggregation of the SOD1 protein. However, the E40K mutation has no effect on human SOD1, suggesting that the aggregation of canine SOD1 due to the E40K mutation is species-specific. Therefore, this research group aimed to elucidate the mechanism of this species-specific aggregation of canine SOD1 caused by the E40K mutation. They discovered that canine SOD1 is inherently more unstable and prone to aggregation than human SOD1 because it has a "gap" in the highly hydrophobic region at the core of the protein. The group also succeeded in reproducing the species-specific aggregation of the SOD1 protein due to the E40K mutation by manipulating the presence or absence of this "gap." This revealed that the inherent vulnerability of canine SOD1, associated with this central "gap," is the factor behind the species-specific aggregation caused by the E40K mutation. The findings of this research are expected to lead to the development of new treatments for DM in the future.
The results of this research were published online in the American scientific journal Journal of Biological Chemistry on May 6, 2023.
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