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タイトル: | Ca²⁺–Calmodulin–Calcineurin Signaling Modulates α‐Synuclein Transmission |
著者: | Ueda, Jun Uemura, Norihito Ishimoto, Tomoyuki ![]() ![]() Taguchi, Tomoyuki ![]() ![]() ![]() Sawamura, Masanori ![]() ![]() ![]() Nakanishi, Etsuro ![]() ![]() Ikuno, Masashi ![]() ![]() Matsuzawa, Shuichi Yamakado, Hodaka ![]() ![]() Takahashi, Ryosuke ![]() ![]() ![]() |
著者名の別形: | 上田, 潤 上村, 紀仁 石本, 智之 田口, 智之 澤村, 正典 中西, 悦郎 生野, 真嗣 松澤, 秀一 山門, 穂高 髙橋, 良輔 |
キーワード: | Parkinson's disease α-synuclein propagation micropinocytosis Ca²⁺–calmodulin–calcineurin signaling |
発行日: | Jun-2023 |
出版者: | Wiley International Parkinson and Movement Disorder Society |
誌名: | Movement Disorders |
巻: | 38 |
号: | 6 |
開始ページ: | 1056 |
終了ページ: | 1067 |
抄録: | BACKGROUND: The intercellular transmission of pathogenic proteins plays a crucial role in the progression of neurodegenerative diseases. Previous research has shown that the neuronal uptake of such proteins is activity-dependent; however, the detailed mechanisms underlying activity-dependent α-synuclein transmission in Parkinson's disease remain unclear. OBJECTIVE: To examine whether α-synuclein transmission is affected by Ca²⁺ -calmodulin-calcineurin signaling in cultured cells and mouse models of Parkinson's disease. METHODS: Mouse primary hippocampal neurons were used to examine the effects of the modulation of Ca²⁺ -calmodulin-calcineurin signaling on the neuronal uptake of α-synuclein preformed fibrils. The effects of modulating Ca²⁺ -calmodulin-calcineurin signaling on the development of α-synuclein pathology were examined using a mouse model injected with α-synuclein preformed fibrils. RESULTS: Modulation of Ca²⁺ -calmodulin-calcineurin signaling by inhibiting voltage-gated Ca²⁺ channels, calmodulin, and calcineurin blocked the neuronal uptake of α-synuclein preformed fibrils via macropinocytosis. Different subtypes of voltage-gated Ca²⁺ channel differentially contributed to the neuronal uptake of α-synuclein preformed fibrils. In wild-type mice inoculated with α-synuclein preformed fibrils, we found that inhibiting calcineurin ameliorated the development of α-synuclein pathology. CONCLUSION: Our data suggest that Ca²⁺ -calmodulin-calcineurin signaling modulates α-synuclein transmission and has potential as a therapeutic target for Parkinson's disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
著作権等: | © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. |
URI: | http://hdl.handle.net/2433/287291 |
DOI(出版社版): | 10.1002/mds.29401 |
PubMed ID: | 37066491 |
出現コレクション: | 学術雑誌掲載論文等 |
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