2021 Fiscal Year Final Research Report
Protective effects of autophagy-related factor Beclin 1 on a-synuclein-induced neurotoxicity
| Project/Area Number |
19K07834
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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 51030:Pathophysiologic neuroscience-related
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| Research Institution | Osaka Medical and Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 神経変性疾患 / 病態生化学 / パーキンソン病 / タンパク質分解 / オートファジー / αシヌクレイン |
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| Outline of Final Research Achievements |
Cell-to-cell transmission of α-synuclein aggregates seems to cause neurodegeneration of Parkinson’s disease (PD). We investigated the contribution of autophagy to α-synuclein metabolism by using knockout (KO) mice of autophagy-inducer Beclin 1. Treatment with rapamycin facilitated extracellular secretion of α-synuclein in mouse primary cortical neurons. Rapamycin-induced α-synuclein secretion was significantly suppressed in primary neurons from Beclin 1 heterozygous KO mice, as compared with those from wild-type littermates. Additionally, Beclin 1 KO mice at 5 months of age accumulated detergent-insoluble α-synuclein in the cerebrum and striatum. These data suggest that autophagy affects intracellular clearance of α-synuclein by modulating α-synuclein secretion in neurons. The autophagy-based machinery of α-synuclein secretion could be a new target to suppress cell-to-cell transmission of α-synuclein in PD.
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| Free Research Field |
神経内科
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| Academic Significance and Societal Importance of the Research Achievements |
αシヌクレインの細胞内クリアランスの異常が、パーキンソン病の神経変性を引き起こすαシヌクレインの凝集体形成と細胞間伝播に関与していると考えられている。今回の研究結果は、オートファジーが従来考えられてきたタンパク質分解のみならず、細胞外分泌を介してαシヌクレインの細胞内クリアランスに寄与していることを示していた。オートファジーによる細胞外分泌の調節機構は、αシヌクレインの凝集体形成および細胞間伝播を修飾するパーキンソン病進行抑制治療の新たな候補と考えられる。
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