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

Mahmood Ali Saleh, Fatima Amer-Sarsour, Asaf Berant, Metsada Pasmanik-Chor, Hila Kobo, Yehonatan Sharabi, Gad D. Vatine*, Avraham Ashkenazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)164-173
Number of pages10
JournalFree Radical Biology and Medicine
Volume213
DOIs
StatePublished - Mar 2024

Funding

FundersFunder number
Aufzien Family Center for the Prevention and Treatment of Parkinson's Disease
DoD CDMRPW81XWH-22-1-0378
Yoran Institute for Human Genome Research
Israel Science Foundation923/22

    Keywords

    • Mitochondrial complex I
    • Neurotoxin
    • Parkinson's disease
    • Peripheral autonomic nervous system
    • Sympathetic neurons

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