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VPS35 D620N mutation impairs neurogenesis and promotes ferroptosis in Parkinson's disease by using molecular docking,
Mei Jiang1,2, Xu Deng1,2, Zijie Qiu1,2
1The Affiliated Dongguan Songshan Lake Central Hospital, Guangdong Medical University, Dongguan, China.
Backgroud:
VPS35, a core component of the retromer complex, has been closely associated with neurodegenerative disorders, particularly Parkinson's disease (PD). The VPS35 D620N mutation has been identified as a pathogenic variant in familial PD. However, the precise mechanisms by which VPS35 and its D620N mutant influence neurogenesis remain poorly understood. This study explores the role of the VPS35 D620N mutation in PD-related neurogenesis.
Methods And Results:
Protein-protein interaction (PPI) and KEGG pathway analyses identified key regulatory molecules, including TP53, AKT1, and SRC, with the PI3K-Akt signaling pathways emerging as central contributors to mutation-induced neurogenic deficits and ferroptosis in PD. Molecular docking analysis demonstrated strong binding affinities between VPS35 D620N and these hub targets, particularly PI3K. Furthermore, molecular dynamics simulations confirmed the stable interaction between VPS35 D620N and key hub proteins. Immunofluorescence staining revealed that the D620N mutation significantly impaired the neurogenic capacity of neural precursor cells both in vivo and in vitro, accompanied by increased cell death. Cellular experiments further revealed that the D620N mutation promoted cell death, increased lipid peroxidation and reactive oxygen species (ROS) levels, reduced the expression of ferroptosis-related proteins such as GPX4, and downregulated components of the PI3K-Akt signaling pathway.
Conclusion:
This study highlights that the VPS35 D620N mutation may impair neurogenesis through ferroptosis mediated by dysregulation of the PI3K-Akt pathway, offering novel mechanistic insights into its role in PD pathogenesis.
Insights
The VPS35 D620N mutation impairs neurogenesis in Parkinson's disease (PD) by inducing ferroptosis via PI3K-Akt pathway dysregulation. This finding offers new insights into PD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- VPS35 is crucial for retromer complex function and linked to neurodegenerative diseases like Parkinson's disease (PD).
- The VPS35 D620N mutation is a known cause of familial PD, but its role in neurogenesis is unclear.
Purpose of the Study:
- To investigate the impact of the VPS35 D620N mutation on neurogenesis in Parkinson's disease.
- To elucidate the molecular mechanisms underlying mutation-induced neurogenic deficits and cell death.
Main Methods:
- Protein-protein interaction (PPI) and KEGG pathway analyses to identify regulatory molecules and pathways.
- Molecular docking and dynamics simulations to assess binding affinities and interactions.
- In vivo and in vitro immunofluorescence staining and cellular experiments to evaluate neurogenic capacity and cell death.
Main Results:
- The VPS35 D620N mutation impairs neurogenesis in neural precursor cells, leading to increased cell death.
- Mutation-induced deficits are associated with ferroptosis, elevated reactive oxygen species (ROS), and lipid peroxidation.
- Downregulation of the PI3K-Akt signaling pathway and ferroptosis-related proteins (e.g., GPX4) was observed.
Conclusions:
- The VPS35 D620N mutation impairs neurogenesis in PD potentially through ferroptosis, driven by PI3K-Akt pathway dysregulation.
- This study provides novel mechanistic insights into the role of VPS35 mutations in Parkinson's disease pathogenesis.
