TY - JOUR
T1 - Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress
AU - Nourse, J. Brucker
AU - Harshefi, Gilad
AU - Marom, Adi
AU - Karmi, Abdelrahaman
AU - Cohen Ben-Ami, Hagit
AU - Caldwell, Kim A.
AU - Caldwell, Guy A.
AU - Treinin, Millet
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/3/19
Y1 - 2021/3/19
N2 - Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease, whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model, we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homolog; MCU-1, a mitochondrial calcium uniporter; PINK-1 (PTEN-induced kinase 1); and PDR-1 (Parkin) are required for nicotine-mediated protection of DNs. Together, our results support involvement of a calcium-modulated, mitochondrial stress-activated PINK1/Parkin-dependent pathway in nicotine-induced neuroprotection. This suggests that nicotine-selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation, and second, their specific expression of D3-receptors.
AB - Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease, whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model, we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homolog; MCU-1, a mitochondrial calcium uniporter; PINK-1 (PTEN-induced kinase 1); and PDR-1 (Parkin) are required for nicotine-mediated protection of DNs. Together, our results support involvement of a calcium-modulated, mitochondrial stress-activated PINK1/Parkin-dependent pathway in nicotine-induced neuroprotection. This suggests that nicotine-selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation, and second, their specific expression of D3-receptors.
KW - Biological Sciences
KW - Molecular Neuroscience
KW - Neuroscience
UR - http://www.scopus.com/inward/record.url?scp=85101033044&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.102140
DO - 10.1016/j.isci.2021.102140
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AN - SCOPUS:85101033044
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 3
M1 - 102140
ER -