Disulfidptosis contributes to rotenone-induced dopaminergic neuron damage

Parkinson's disease is a neurodegenerative disorder whose pathogenesis remains incompletely understood. Rotenone exposure is reportedly associated with Parkinson's disease. In addition, Disulfidptosis is a newly identified form of cell death. Interestingly, an analysis of the Gene Expression Omnibus Parkinson's disease database indicated that approximately 30 genes that are significantly altered in patients with Parkinson's disease are associated with Disulfidptosis. In the present study, using proteomics, a number of important proteins related to Disulfidptosis were identified as significantly altered in rotenone-exposed dopaminergic neurons. Further analysis revealed that the formation of abnormal disulfide bonds was also increased in rotenone-exposed dopaminergic neurons. The protein expression of solute carrier family 7 member 11 and Amino acid Transporter heavy chain SLC3A2 was upregulated in rotenone-exposed dopaminergic neurons, and was correlated with extracellular Matrix Protein 1 protein expression. These findings indicate that in rotenone-exposed PC12 cells, a cystine influx is triggered, and the conversion of cystine to cysteine is inhibited by a reduction in the oxidized nicotinamide adenine dinucleotide phosphate/reduced nicotinamide adenine dinucleotide phosphate ratio, which leads to cystine accumulation. This excessive accumulation of cystine then promotes the formation of abnormal disulfide bonds in cells, ultimately resulting in Disulfidptosis of rotenone-exposed dopaminergic neurons. In this process, the Rasrelated C3 botulinum toxin substrate 1/WAVE regulatory complex/actin-related protein 2/3 pathway was markedly activated, which led to the collapse of the Cytoskeleton in rotenone-exposed PC12 cells. Together, our findings suggest that rotenone may induce solute carrier family 7 member 11 expression through extracellular Matrix Protein 1 activation to cause cystine accumulation, which results in Disulfidptosis characterized by Cytoskeleton collapse. The present results provide new perspectives for research into neurodegenerative diseases.

Parkinson’s disease; SLC7A11; cell death; cystine; cytoskeleton; disulfidptosis; dopaminergic neuron; neurodegeneration; oxidative stress; rotenone.