Inhibitor Development for α-Synuclein Fibril’s Disordered Region to Alleviate Parkinson’s Disease Pathology
The amyloid fibrils of α-synuclein (α-syn) are crucial in the pathology of Parkinson's disease (PD), with the intrinsically disordered region (IDR) of its C-terminal playing a key role in interacting with receptors like LAG3 and RAGE, facilitating pathological neuronal spread and inflammation. In this study, we identified Givinostat (GS) as an effective inhibitor that disrupts the interaction of α-syn fibrils with receptors such as LAG3 and RAGE through high-throughput screening. By exploring the structure-activity relationship and optimizing GS, we developed several lead compounds, including GSD-16-24. Utilizing solution-state and solid-state NMR, along with cryo-EM techniques, we demonstrated that GSD-16-24 binds directly to the C-terminal IDR of α-syn monomer and fibril, preventing the fibril from binding to the receptors. Furthermore, GSD-16-24 significantly inhibits the association of α-syn fibrils with membrane receptors, thereby reducing neuronal propagation and pro-inflammatory effects of α-syn fibrils. Our findings introduce a novel approach to mitigate the pathological effects of α-syn fibrils by targeting their IDR with small molecules, offering potential leads for the development of clinical drugs to treat PD.
Authors
- Huaijiang Xiang (ORCID: https://orcid.org/0000-0003-1044-6359)
- Martin Li (ORCID: https://orcid.org/0000-0002-6134-5622)
- Shenqing Zhang (ORCID: https://orcid.org/0000-0002-6849-6976)
- Bo Sun (ORCID: https://orcid.org/0000-0002-4590-7795)
- ShengQi Xiang (ORCID: https://orcid.org/0000-0002-6874-4925)
- Youqi Tao
- Shuyi Zeng
- Caiwei Song
- Shiran Lv
- Zeyun Zhu
- Qianhui Xu (ORCID: https://orcid.org/0000-0002-9175-8532)
- Cong Liu (ORCID: https://orcid.org/0000-0003-3425-6672)
- Dan Li (ORCID: https://orcid.org/0000-0002-1609-1539)
- Li Tan (ORCID: https://orcid.org/0000-0002-1199-9046)
- Juan Li (ORCID: https://orcid.org/0009-0007-5172-5780)
- Shengnan Zhang (ORCID: https://orcid.org/0000-0003-1051-7196)
- Haonan Xiao (ORCID: https://orcid.org/0000-0002-2243-7364)
- Cheng Yan (ORCID: https://orcid.org/0009-0000-2568-1365)
Institutions
- University of Science and Technology of China (CN)
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Shanghai Advanced Research Institute (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Interdisciplinary Research Center of Biology and Chemistry (CN)
- State Key Laboratory of Chemical Engineering (CN)
- Institute for Advanced Study (DE)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1021/jacs.4c08869
- Citations
- 27
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 9.97
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China