TY - JOUR
T1 - Chronic and acute exposure to rotenone reveals distinct Parkinson's disease-related phenotypes in human iPSC-derived peripheral neurons
AU - Saleh, Mahmood Ali
AU - Amer-Sarsour, Fatima
AU - Berant, Asaf
AU - Pasmanik-Chor, Metsada
AU - Kobo, Hila
AU - Sharabi, Yehonatan
AU - Vatine, Gad D.
AU - Ashkenazi, Avraham
N1 - Publisher Copyright: © 2024 The Author(s)
PY - 2024/3/1
Y1 - 2024/3/1
N2 - 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.
AB - 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.
KW - Mitochondrial complex I
KW - Neurotoxin
KW - Parkinson's disease
KW - Peripheral autonomic nervous system
KW - Sympathetic neurons
UR - http://www.scopus.com/inward/record.url?scp=85183095452&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.freeradbiomed.2024.01.016
DO - https://doi.org/10.1016/j.freeradbiomed.2024.01.016
M3 - مقالة
C2 - 38246514
SN - 0891-5849
VL - 213
SP - 164
EP - 173
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
ER -