Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

Abstract

Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease (PD), 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 DNexpressed nAChRs. We find that DOP-2, a D3-receptor homolog, MCU-1, a mitochondrial calcium uniporter, and PINK-1, PTEN-induced kinase 1, are required for nicotine-mediated protection of DNs. Together, our results support involvement of calcium-dependent mitochondrial stress activation of PINK-1 in nicotine-dependent neuroprotection. This suggests that nicotine's 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, to their specific expression of D3 receptors.Epidemiological studies show that tobacco smoking reduces the prevalence of Parkinson's disease (PD) (Li et al., 2015). A hallmark of PD is degeneration of substantia nigra dopaminergic neurons (DNs). Effects of tobacco smoking on degeneration of these neurons may depend on tobacco-derived nicotine and on nicotinic acetylcholine receptors (nAChRs). Support for this hypothesis comes from several lines of evidence. These include: i)