Inhibition of α-synuclein aggregation by MCC950 attenuates dopaminergic neuronal damage in MN9D cells

  • Eur J Pharmacol. 2025 Aug 15:1001:177774. doi: 10.1016/j.ejphar.2025.177774.
Huiwen Gao  1 ,  Yingneng Liang  1 ,  Mengfei Wang  1 ,  Wen Li  2 ,  Wei Zheng  2 ,  Zitong Wang  2 ,  Guangqiang Sun  3 ,  Hongchun Liu  3 ,  Ming Liu  4 ,  Yu Zhang  5
Affiliations
  • 1. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China.
  • 2. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China.
  • 4. Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, Shandong, China. Electronic address: [email protected].
PMID: 40436242 DOI: 10.1016/j.ejphar.2025.177774
Abstract

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the pathological aggregation of α-synuclein, which drives neurodegeneration. The NLRP3 inflammasome inhibitor MCC950 has shown neuroprotective effects in various PD models, but its direct impact on α-synuclein Aggregation remains unclear. Here, we investigated the effects of MCC950 in an α-synuclein-overexpressing MN9D dopaminergic neuronal model. MCC950 significantly alleviated α-synuclein-induced neuronal damage, as evidenced by improved cell viability, reduced Apoptosis, and downregulated tumor necrosis factor-alpha (TNF-α) 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 α-synuclein, inhibiting its aggregation. Additionally, MCC950 upregulated heat shock protein 70 (HSP70), a molecular chaperone that suppresses α-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 α-synuclein Aggregation, offering a promising strategy for treating PD and related α-synucleinopathies.

Keywords
MCC950; Neuroprotection; Parkinson's disease; α-synuclein.
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