| 研究課題/領域番号 |
22K15377
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| 研究種目 |
若手研究
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| 配分区分 | 基金 |
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| 審査区分 |
小区分48040:医化学関連
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| 研究機関 | 新潟大学 |
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研究代表者 |
アニシモフ セルゲイ 新潟大学, 医歯学系, 特任助教 (70867572)
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| 研究期間 (年度) |
2022-04-01 – 2025-03-31
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| 研究課題ステータス |
交付 (2023年度)
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| 配分額 *注記 |
4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円)
2023年度: 2,470千円 (直接経費: 1,900千円、間接経費: 570千円)
2022年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
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| キーワード | USP10 / synuclein / Autophagy / Parkinson's disease / Synuclein / Neurodegeneration / Synucelin / G3BP1 / Aggresome |
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| 研究開始時の研究の概要 |
Neuronal death in Parkinson’s disease (PD) correlates with accumulation of toxic protein oligomers in cells. Project aims to elucidate inactivation mechanism of oligomer toxicity regulated by autophagy and aggresome in PD, using neuronal cells, model mice, and PD patient samples.
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| 研究実績の概要 |
We investigate how neurons counteract the harmful effects of toxic α-synuclein oligomers in Parkinson's disease. The accumulation of these oligomers in cells, due to excessive α-synuclein levels, is associated with neuronal death and disease progression. We uncovered that lysosomal degradation of α-synuclein and the formation of aggresomes containing α-synuclein play a crucial role in preventing the formation and neutralizing the toxicity of these oligomers in neurons. We identified that these processes are co-regulated by three proteins: USP10, G3BP1, and p62. We found that USP10 regulates the selective degradation of α-synuclein, as well as potentially other disease-related proteins, through a shared mechanism.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
We are preparing a paper for submission. We utilized chemical inhibitors of USP10 deubiquitinating enzyme, enzyme activity-inactive mutants of USP10, and specially developed protein degradation probes to support the newly discovered mechanism of targeted degradation of α-synuclein via USP10.
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| 今後の研究の推進方策 |
(1) We are currently in the final stages of submitting the paper. The main plans for the future are to move forward with the publication of the paper and to conduct experiments based on the reviewers' comments.
(2) Based on our recent findings, we will analyze the involvement of the mTOR pathway, a major regulator of autophagy, in the degradation of α-synuclein by USP10 and G3BP1.
(3) We will conduct additional rescue experiments to assess the activities of G3BP1 and USP10 in cells, further supporting our model.
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