2018 Fiscal Year Final Research Report
Understanding of polymerization mechanism based on three-dimensional structural information of extension end of amyloid fibril toward to drug discovery
| Project/Area Number |
17K15441
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Physical pharmacy
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| Research Institution | Center for Novel Science Initatives, National Institutes of Natural Sciences (2018)
Institute for Molecular Science (2017) |
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Principal Investigator |
Yagi Maho 大学共同利用機関法人自然科学研究機構(新分野創成センター、アストロバイオロジーセンター、生命創成探究, 生命創成探究センター, 助教 (40608999)
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| Research Collaborator |
NISHIMURA katsuyuki
MURATA kazuyoshi
OKUMURA hisashi
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Keywords | アミロイド線維 / アミロイドβ / 核磁気共鳴 / 電子顕微鏡 |
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| Outline of Final Research Achievements |
In order to obtain three-dimensional structural information of extension end of amyloid fibril toward to drug discovery, we attempted to characterize the amyloids formed under microgravity environment. Thioflavin T assay suggested amyloid fibrils formed more slowly in space than on the ground. Solid-state NMR and cryo-EM data showed the fibril structure formed under microgravity environment was different from that formed on the ground. Additionally, to understand the effects of the interface on oligomerization of Aβ, we performed MD simulations and NMR experiment for an Aβ40 monomer in the presence and absence of the hydrophilic/hydrophobic interface such as ganglioside membrane. We found that the hydrophobic residues of Aβ40 bound to the interface stably and Aβ40 formed a hairpin structure at the interface more readily than in bulk water. From these results, we discussed the acceleration mechanism of the oligomer formation at the interface.
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| Free Research Field |
生物物理学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の成果は、微小重力環境および膜環境におけるAβのアミロイド線維形成メカニズムの一端を明らかにするものである。今後、得られた構造情報に基づいてアミロイド線維の伸長を特異的に阻害する化合物を設計する糸口を与え、アルツハイマー病やパーキンソン病をはじめとするアミロイド線維関連疾患の予防や治療に向けた創薬研究への可能性を切り拓くものと予想される。またアミロイド線維伸長に限らず、オリゴマー形成メカニズムに関しても理解を促すものとなる。こうしたストラテジーを構築することができれば、神経変性疾患の発症機構全般に通じるような普遍的な分子病態を解明することにつながることが期待される。
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