| Project/Area Number |
18K07510
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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 52020:Neurology-related
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| Research Institution | Juntendo University |
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Principal Investigator |
Tsunemi Taiji 順天堂大学, 医学(系)研究科(研究院), 准教授 (50401344)
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| Co-Investigator(Kenkyū-buntansha) |
赤松 和土 順天堂大学, 医学(系)研究科(研究院), 教授 (60338184)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | エキソソーム / パーキンソン病 / αシヌクレイン / レヴィ小体 / アストロサイト / アルファシヌクレイン / ATP13A2 / Lewy小体 / ライブイメージング / 超解像顕微鏡 / Kufor-Rakeb症候群 |
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| Outline of Final Research Achievements |
To explore the relationship between exosomes and propagation of alpha-synuclein (a-syn) in brains, we used Atp13a2 null mice and lenti-virus mediated overexpression of ATP13A2, which is an endolysosomal protein and play a role for generation of exosomes. Although, after inoculation of a-syn fibrils, no differences were observed in the development of Lewy body-like pathology between wild-type and Atp13a2 null mice, this pathology was attenuated at regions far away from the inoculated site by ATP13A2 overexpression. Further studies revealed that PFFs were first taken up by glia, and then later accumulated in neurons. This suggests that the development of Lewy body-like pathology takes certain time, and requires glia’s a-syn uptake.
We also discovered that astrocytes can secrete more exosomes and PFF compared to neurons, attenuate neuronal a-syn accumulation and block a-syn transfer between neurons. This suggests that glia can be a novel therapeutic target for Parkinson’s disease.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、エキソソームがαシヌクレインの脳内伝播とLewy小体病理形成に深く関与していることが明らかとなりました。また、アストロサイトはより多くのエキソソームを分泌し、αシヌクレインを分泌することで神経細胞の蓄積を軽減するのみならず神経細胞間のαシヌクレインの伝播を抑制しました。以上の結果はグリア細胞のエキソソームがパーキンソン病の新たな治療ターゲットとなる可能性を示しています。
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