2022 Fiscal Year Final Research Report
Molecular function and a pathological role of LMTK1, a novel factor regulating spine formation
| Project/Area Number |
19K06942
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 46030:Function of nervous system-related
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| Research Institution | Tokyo Metropolitan University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
飯島 香奈絵 (安藤香奈絵) 東京都立大学, 理学研究科, 准教授 (40632500)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | 神経細胞 / 小胞輸送 / エンドソーム / LMTK1 / 記憶形成 / アルツハイマー病 / BACE1 / APP |
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| Outline of Final Research Achievements |
We have been investigating the role of Lemur kinase 1 (LMTK1) in recycling endosome trafficking in neurons and reported previously that LMTK1 regulates axon outgrowth and spine formation via Rab11 activity. Here, we studied its in vivo function using LMTK1 knockout mouse and a pathological role in Alzheimer’s disease. We found that mice lacking LMTK1 show normal spatial and fear-conditioning memories, while the knockout of LMTK1 induced hyperactivity similar to those of Attention Deficient Hyperactivity Disorder (ADHD). We also observed that LMTK1 regulated the intracellular localization and trafficking of bata-secretase BACE1, but not amyloid precursor protein (APP), in COS-7 cells and primary neurons, resulting in the increased bata-cleavage of APP although amyloid beta peptide itself was not increased. We also found that LMTK1 was reduced in brains of Alzheimer’s disease patients, supporting the notion that LMTK1 and Rab11 are risk factors of neurodegenerative diseases.
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| Free Research Field |
神経生化学
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| Academic Significance and Societal Importance of the Research Achievements |
神経細胞内における小胞輸送は軸索伸長やスパイン形成を介して、神経機能に影響を及ぼしているが詳細な分子機構は不明である。リサイクリングエンドソームの新規制御因子であるLMTK1の脳機能における生理的な役割と神経変性疾患にかかわる病理的な役割を探求した結果、LMTK1の欠失は記憶形成には影響を与えないが自閉症様の症状を示すこと、LMTK1活性はBACE1の細胞内輸送制御を介してアルツハイマー病発症に関わる可能性などが示唆された。LMTK1の変異は発達障害にも関わる可能性が示唆されており、今後その役割についてより詳細な研究が必要である。
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