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Disulfidptosis contributes to rotenone-induced dopaminergic neuron damage
1Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
Neural Regeneration Research
|October 31, 2025
Summary
Rotenone exposure triggers cystine accumulation and abnormal disulfide bonds, leading to disulfidptosis (cell death) in dopaminergic neurons, offering new insights into Parkinson's disease pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Parkinson's disease (PD) pathogenesis is not fully understood.
- Rotenone exposure is linked to PD.
- Disulfidptosis is a newly identified cell death pathway implicated in PD.
Purpose of the Study:
- Investigate the role of disulfidptosis in rotenone-induced dopaminergic neurodegeneration.
- Elucidate the molecular mechanisms underlying rotenone-induced cell death.
Main Methods:
- Proteomic analysis of rotenone-exposed dopaminergic neurons.
- Gene Expression Omnibus (GEO) database analysis for PD-associated genes.
- Assessment of disulfide bond formation and protein expression.
Main Results:
- Proteomics identified altered disulfidptosis-related proteins in rotenone-exposed neurons.
- Increased abnormal disulfide bond formation and cystine accumulation were observed.
- Upregulation of solute carrier family 7 member 11 (SLC7A11) and SLC3A2 correlated with extracellular matrix protein 1 (ECM1).
- The Ras-related C3 botulinum toxin substrate 1 (RAC1)/WAVE regulatory complex/actin-related protein 2/3 (ARP2/3) pathway activation led to cytoskeleton collapse.
Conclusions:
- Rotenone induces cystine accumulation via SLC7A11 upregulation, potentially mediated by ECM1, leading to disulfidptosis.
- Disulfidptosis in this model is characterized by cytoskeleton collapse.
- Findings provide novel perspectives on neurodegenerative disease mechanisms and potential therapeutic targets.
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