Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA
Gilad Harshefi
Department of Medical Neurobiology, Hebrew University – Hadassah Medical School, Jerusalem 91120, Israel
Adi Marom
Department of Medical Neurobiology, Hebrew University – Hadassah Medical School, Jerusalem 91120, Israel
Abdelrahaman Karmi
Department of Medical Neurobiology, Hebrew University – Hadassah Medical School, Jerusalem 91120, Israel
Hagit Cohen Ben-Ami
Department of Medical Neurobiology, Hebrew University – Hadassah Medical School, Jerusalem 91120, Israel
Kim A. Caldwell
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence in the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
Guy A. Caldwell
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA; Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, Nathan Shock Center of Excellence in the Basic Biology of Aging, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
Millet Treinin
Department of Medical Neurobiology, Hebrew University – Hadassah Medical School, Jerusalem 91120, Israel; Corresponding author
Summary: 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.
