Chronic and acute exposure to rotenone lead to distinct Parkinson’s disease-related phenotypes in human iPSC-derived peripheral neurons

Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). While the majority of PD cases are sporadic with no identified PD-associated genes involved, epidemiological and animal model studies suggest an association with pesticides and other environmental toxins but underlying cellular mechanisms affecting the human P-ANS is unclear. Here, we mapped the global transcriptome changes in human induced-pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons followed by exposure to the PD-related pesticide, rotenone. Surprisingly, we revealed distinct transcriptome profiles between acute and chronic exposure to rotenone. In the acute stage, there was a down regulation of specific cation channel genes mediating action potential signaling, while in the chronic stage, the human P-ANS neurons exhibited dysregulation of anti-apoptotic and Golgi apparatus-related pathways. Moreover, we identified the sodium voltage-gated channel subunit SCN3A/Nav1.3 as a potential biomarker in human P-ANS neurons associated with PD. Our analysis of the rotenone-altered coding and non-coding genome of human P-ANS neurons may thus provide insight into the pathological signaling events that occur in the sympathetic neurons during PD progression. Here we established a model of human P-ANS in PD by utilizing the pesticide, rotenone that is associated with increased PD risk, inhibits complex I of the mitochondrial respiratory chain, and reproduces PD pathological staging as found in patients. By applying transcriptomics approach, we uncover molecular mechanisms by which rotenone causes pathology in human P-ANS neurons involving both functional abnormalities and specific neurodegeneration signaling.