2022 Fiscal Year Research-status Report
Inactivation mechanism of alpha-synuclein oligomer toxicity in Parkinson's disease
| Project/Area Number |
22K15377
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| Research Institution | Niigata University |
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Principal Investigator |
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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| Project Period (FY) |
2022-04-01 – 2024-03-31
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| Keywords | USP10 / Synuclein / Neurodegeneration |
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| Outline of Annual Research Achievements |
In our study, we investigate how neurons counteract the harmful effects of toxic α-synuclein oligomers in Parkinson's disease. The accumulation of these oligomers, which occurs due to excessive α-synuclein levels in cells, is associated with neuronal death and disease progression. Our research has uncovered that lysosomal degradation and the formation of aggresomes 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 discovered USP10 activity to regulate selective degradation of α-synuclein, as well as potentially other disease-related proteins through shared mechanism.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We conducted an analysis of the activity of USP10, G3BP1, and p62 in regulating the levels, oligomerization, and toxicity of both wild-type α-synuclein and its disease-associated mutants in neuronal cells. We have developed specialized probes to analyze the newly found mechanism of targeted degradation of α-synuclein by USP10.
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| Strategy for Future Research Activity |
(1) We have developed specialized probes that utilize photo-activation and halo-tagging techniques to investigate specific lysosomal degradation processes. We will utilize these probes to gather information on the activity of USP10 in the targeted autophagic degradation of α-synuclein in neuronal cells. Additionally, we aim to investigate whether USP10 plays a similar role in preventing the aggregation of other disease-associated proteins.
(2) USP10 is an enzyme with deubiquitinating activity and is known to have a broad range of substrates. We plan to utilize a catalytically inactive mutant of USP10 to investigate the involvement of its enzymatic activity in regulating the degradation of α-synuclein in cells.
(3) We plan to measure the levels of G3BP1, USP10, p62, α-synuclein, lysosomal degradation-related proteins, and aggresome-associated proteins in the brains of Parkinson's disease and Alzheimer's disease patients. Additionally, we will investigate the specific modifications of these proteins using techniques such as Western blotting and immunostaining.
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| Causes of Carryover |
The first year of the project was primarily intended to generate original data and define the direction of the research. Unspent budget will be used to conduct targeted experiments to confirm the original findings of the first year in order to achieve the research goals
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