2023 Fiscal Year Research-status Report
Inactivation mechanism of alpha-synuclein oligomer toxicity in Parkinson's disease
| Project/Area Number |
22K15377
|
|---|
| Research Institution | Niigata University |
|---|
Principal Investigator |
アニシモフ セルゲイ 新潟大学, 医歯学系, 特任助教 (70867572)
|
|---|
| Project Period (FY) |
2022-04-01 – 2025-03-31
|
| Keywords | USP10 / synuclein / Autophagy / Parkinson's disease |
|---|
| Outline of Annual Research Achievements |
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.
|
| 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 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.
|
| Strategy for Future Research Activity |
(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.
|
| Causes of Carryover |
We are preparing a paper for submission. The unspent budget will be used for conducting final experiments based on reviewers' comments
|
