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

• Published in: Free radical biology & medicine Vol. 213; pp. 164 - 173
• Main Authors: Saleh, Mahmood Ali, Amer-Sarsour, Fatima, Berant, Asaf, Pasmanik-Chor, Metsada, Kobo, Hila, Sharabi, Yehonatan, Vatine, Gad D., Ashkenazi, Avraham
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2024
• Subjects: Mitochondrial complex I; Neurotoxin; Parkinson's disease; Peripheral autonomic nervous system; Sympathetic neurons; Mitochondrial complex I; Parkinson's disease; Sympathetic neurons; Peripheral autonomic nervous system; Neurotoxin
• DOI: 10.1016/j.freeradbiomed.2024.01.016
• EISSN: 1873-4596
• ISSN: 0891-5849

Peripheral autonomic nervous system (P-ANS) dysfunction is a critical non-motor phenotype of Parkinson's disease (PD). The majority of PD cases are sporadic and lack identified PD-associated genes involved. Epidemiological and animal model studies suggest an association with pesticides and other environmental toxins. However, the cellular mechanisms underlying toxin induced P-ANS dysfunctions remain unclear. Here, we mapped the global transcriptome changes in human induced pluripotent stem cell (iPSC) derived P-ANS sympathetic neurons during inhibition of the mitochondrial respiratory chain by the PD-related pesticide, rotenone. 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, known to mediate electrophysiological activity, 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 transcriptome of human P-ANS neurons may thus provide insight into the pathological signaling events in the sympathetic neurons during PD progression.
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•A human model of the peripheral autonomic nervous system (P-ANS) in Parkinson's disease (PD) was developed.•Inhibiting the mitochondrial electron transport chain by rotenone alters specific transcriptional networks in P-ANS neurons.•In these neurons, several cation channels including SCN3A associated with excitability are downregulated by rotenone.•A new repertoire of non-coding genes that may be related to PD was identified in P-ANS neurons.