ダウンロード数: 298
このアイテムのファイル:
ファイル | 記述 | サイズ | フォーマット | |
---|---|---|---|---|
pnas.1421182112.pdf | 5.19 MB | Adobe PDF | 見る/開く |
タイトル: | Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly. |
著者: | 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 |
著者名の別形: | 星, 美奈子 |
キーワード: | NMR computational modeling abnormal protein–protein interaction in synapse hyperexcitotoxicity protein–protein interaction inhibitors |
発行日: | 11-Aug-2015 |
出版者: | National Academy of Sciences |
誌名: | Proceedings of the National Academy of Sciences of the United States of America |
巻: | 112 |
号: | 32 |
開始ページ: | E4465 |
終了ページ: | E4474 |
抄録: | 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 Asn(879) and Trp(880) 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. |
記述: | アルツハイマー病で起こる神経細胞死の新たなターゲット分子の発見 -神経細胞死の新たな分子メカニズム解明による革新的治療法の開発に期待-. 京都大学プレスリリース. 2015-08-14. |
著作権等: | © 2015 National Academy of Sciences. This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。 |
URI: | http://hdl.handle.net/2433/199653 |
DOI(出版社版): | 10.1073/pnas.1421182112 |
PubMed ID: | 26224839 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2015-08-14 |
出現コレクション: | 学術雑誌掲載論文等 |
このリポジトリに保管されているアイテムはすべて著作権により保護されています。