Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress


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.

Multidisciplinary Sciences
Nourse, J. B., Jr., Harshefi, G., Marom, A., Karmi, A., Cohen Ben-Ami, H., Caldwell, K. A., Caldwell, G. A., & Treinin, M. (2021). Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress. In iScience (Vol. 24, Issue 3, p. 102140). Elsevier BV.