Nicotine prevents alpha-synuclein accumulation in mouse and human iPSC-derived dopaminergic neurons through activation of the dopamine D3- acetylcholine nicotinic receptor heteromer

• Published in: Neurobiology of disease 2019-09, Vol.129, p.1-12
• Main Authors: Bono, Federica, Mutti, Veronica, Savoia, Paola, Barbon, Alessandro, Bellucci, Arianna, Missale, Cristina, Fiorentini, Chiara
• Format: Article
• Language: English
• Subjects: Alpha-synuclein; alpha-Synuclein - drug effects; Animals; Cells, Cultured; Dopamine D3 receptor; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Heteromerization; Human induced pluripotent stem cell (hiPSC); Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotection; Neuroprotective Agents - pharmacology; Nicotine; Nicotine - pharmacology; Nicotinic receptor; Proximity Ligation Assay (PLA); Receptors, Dopamine D3 - drug effects; Receptors, Dopamine D3 - metabolism; Receptors, Nicotinic - drug effects; Receptors, Nicotinic - metabolism; Ubiquitin-proteasome system (UPS)
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.04.017

We recently found that in mouse dopaminergic neurons, the heteromer formed by the dopamine D3 receptor (D3R) and the β2 subunit of acetylcholine nicotinic receptor (nAChR) exerts neurotrophic effects when activated by nicotine, leading to neurons with enlarged cell bodies and increased dendrite arborization. Beside this action, we now show that nicotine, by activating the D3R-nAChR heteromer, protects dopaminergic neurons against neuronal injury. In primary cultures of mouse dopaminergic neurons, in fact, the ability of nicotine to inhibit both the pathological accumulation of alpha-synuclein induced by glucose deprivation and the consequent morphological defects were strongly prevented by disrupting the D3R-nAChR heteromer with specific interfering TAT-peptides; the relevance of the phosphoinositide 3-kinase (PI3K) intracellular signaling in mediating nicotine prevention of alpha-synuclein aggregation has been also demonstrated. Moreover, the ability of nicotine in restoring the ubiquitin-proteasome system has been found as a mechanism contributing to the neuroprotective properties of nicotine. By using the proximity ligation assay, we have shown that the D3R-nAChR heteromer is also expressed in human dopaminergic neurons derived from induced pluripotent stem cells. In this human cell model, nicotine exerts neuroprotective effects specifically acting through the D3R-nAChR complex thus indicating that this heteromer is a relevant molecular effector involved in the protection of human dopaminergic neurons. •Nicotine protects mouse and human dopaminergic neurons against neuronal injury.•D3R-nAChR heteromer is required for nicotine-induced neuroprotection.•Restoring the ubiquitin-proteasome system is required for nicotine neuroprotection.