Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly
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 caus...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2015
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| Online Access: | https://hdl.handle.net/10356/81180 http://hdl.handle.net/10220/39149 |
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| author | 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 |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences 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 |
| author_sort | Ohnishi, Takayuki |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:42:06Z |
| format | Journal Article |
| id | ntu-10356/81180 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:42:06Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/811802022-02-16T16:30:25Z Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly 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 School of Physical and Mathematical Sciences Abnormal protein–protein interaction in synapse Hyperexcitotoxicity NMR Computational modeling Protein-protein interaction inhibitors 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. 2015-12-18T01:57:39Z 2019-12-06T14:23:05Z 2015-12-18T01:57:39Z 2019-12-06T14:23:05Z 2015 Journal Article 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. https://hdl.handle.net/10356/81180 http://hdl.handle.net/10220/39149 10.1073/pnas.1421182112 26224839 en Proceedings of the National Academy of Sciences of the United States of America © 2015 The Authors (Published by National Academy of Sciences). 10 p. |
| spellingShingle | Abnormal protein–protein interaction in synapse Hyperexcitotoxicity NMR Computational modeling Protein-protein interaction inhibitors 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 Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title_full | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title_fullStr | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title_full_unstemmed | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title_short | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly |
| title_sort | na k atpase α3 is a death target of alzheimer patient amyloid β assembly |
| topic | Abnormal protein–protein interaction in synapse Hyperexcitotoxicity NMR Computational modeling Protein-protein interaction inhibitors |
| url | https://hdl.handle.net/10356/81180 http://hdl.handle.net/10220/39149 |
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