Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells
文献类型：期刊论文
| 作者 | Gao, Huiwen1,3; Liang, Yingneng1,3; Wang, Mengfei1,3; Li, Wen1; Zheng, Wei1; Wang, Zitong1; Sun, Guangqiang1,2; Liu, Hongchun1,2 ; Liu, Ming1,3; Zhang, Yu1,2
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| 刊名 | EUROPEAN JOURNAL OF PHARMACOLOGY
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| 出版日期 | 2025-08-15 |
| 卷号 | 1001页码:10 |
| 关键词 | alpha-synuclein MCC950 Parkinson's disease Neuroprotection |
| ISSN号 | 0014-2999 |
| DOI | 10.1016/j.ejphar.2025.177774 |
| 英文摘要 | Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the pathological aggregation of alpha-synuclein, which drives neurodegeneration. The NLRP3 inflammasome inhibitor MCC950 has shown neuroprotective effects in various PD models, but its direct impact on alpha-synuclein aggregation remains unclear. Here, we investigated the effects of MCC950 in an alpha-synuclein-overexpressing MN9D dopaminergic neuronal model. MCC950 significantly alleviated alpha-synuclein-induced neuronal damage, as evidenced by improved cell viability, reduced apoptosis, and downregulated tumor necrosis factor-alpha (TNF-alpha) expression. Proteomic analysis revealed that MCC950 modulates protein processing in the endoplasmic reticulum (ER), potentially alleviating stress-induced protein misfolding. Molecular docking and biochemical assays demonstrated that MCC950 directly binds to the C-terminal region of alpha-synuclein, inhibiting its aggregation. Additionally, MCC950 upregulated heat shock protein 70 (HSP70), a molecular chaperone that suppresses alpha-synuclein oligomerization. Notably, the neuroprotective effects of MCC950 were independent of autophagy modulation or NLRP3 inflammasome inhibition in this model. These findings highlight MCC950 as a multi-target therapeutic agent that directly inhibits alpha-synuclein aggregation, offering a promising strategy for treating PD and related alpha-synucleinopathies. |
| 资助项目 | Key R&D Program of Shandong Province, China[2024CXPT029] ; Shandong Laboratory Program[SYS202205] ; Shandong Provincial Natural Science Foundation[ZR2024QH615] ; National Natural Science Foundation of China[82104140] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001502171400005 |
| 出版者 | ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318171]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Liu, Ming; Zhang, Yu |
| 作者单位 | 1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Minist Educ, Qingdao 266003, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gao, Huiwen,Liang, Yingneng,Wang, Mengfei,et al. Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2025,1001:10. |
| APA | Gao, Huiwen.,Liang, Yingneng.,Wang, Mengfei.,Li, Wen.,Zheng, Wei.,...&Zhang, Yu.(2025).Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells.EUROPEAN JOURNAL OF PHARMACOLOGY,1001,10. |
| MLA | Gao, Huiwen,et al."Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells".EUROPEAN JOURNAL OF PHARMACOLOGY 1001(2025):10. |
入库方式： OAI收割
来源：上海药物研究所
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