摘要：SummaryTobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson’s disease, whose hallmark is degeneration ofsubstantia nigradopaminergic neurons (DNs). We useC. elegansas 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 ofsubstantia nigraDNs 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.Graphical abstractDisplay OmittedHighlights•Establishment of aC. elegansmodel for nicotine-induced neuroprotection•Dopaminergic neuron-expressed nAChRs exhibit conserved functions•Nicotine-induced nAChR- and D3R-dependent signaling is neuroprotectivein vivo•Nicotine-induced protection involves mediators of mitochondrial quality controlBiological Sciences; Neuroscience; Molecular Neuroscience
