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https://hdl.handle.net/10356/81180
Title: | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly | Authors: | Ohnishi, Takayuki Yanazawa, Masako Sasahara, Tomoya Kitamura, Yasuki Hiroaki, Hidekazu Fukazawa, Yugo Kii, Isao Nishiyama, Takashi Kakita, Akiyoshi Takeda, Hiroyuki Takeuchi, Akihide Arai, Yoshie Ito, Akane Komura, Hitomi Hirao, Hajime Satomura, Kaori Inoue, Masafumi Muramatsu, Shin-ichi Matsui, Ko Tada, Mari Sato, Michio Saijo, Eri Shigemitsu, Yoshiki Sakai, Satoko Umetsu, Yoshitaka Goda, Natsuko Takino, Naomi Takahashi, Hitoshi Hagiwara, Masatoshi Sawasaki, Tatsuya Iwasaki, Genji Nakamura, Yu Nabeshima, Yo-ichi Teplow, David B. Hoshi, Minako |
Keywords: | Abnormal protein–protein interaction in synapse Hyperexcitotoxicity NMR Computational modeling Protein-protein interaction inhibitors |
Issue Date: | 2015 | Source: | Ohnishi, T., Yanazawa, M., Sasahara, T., Kitamura, Y., Hiroaki, H., Fukazawa, Y., et al. (2015). Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. Proceedings of the National Academy of Sciences, 112(32), 4465-4474. | Series/Report no.: | Proceedings of the National Academy of Sciences of the United States of America | Abstract: | Neurodegeneration correlates with Alzheimer’s disease (AD) symptoms, but the molecular identities of pathogenic amyloid β-protein (Aβ) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aβ oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na+/K+-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aβ–derived “thorns” responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn879 and Trp880 is essential for ASPD–NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD–NAKα3 interaction. | URI: | https://hdl.handle.net/10356/81180 http://hdl.handle.net/10220/39149 |
DOI: | 10.1073/pnas.1421182112 | Schools: | School of Physical and Mathematical Sciences | Rights: | © 2015 The Authors (Published by National Academy of Sciences). | Fulltext Permission: | none | Fulltext Availability: | No Fulltext |
Appears in Collections: | SPMS Journal Articles |
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