Nicotine-mediated effects in neuronal and mouse models of synucleinopathy
IntroductionAlpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson’s disease. The plant alkaloid “nicotine” was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear....
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2023.1239009/full |
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| author | Mohamed Bilal Fares Omar Alijevic Stephanie Johne Cassia Overk Makoto Hashimoto Athanasios Kondylis Anthony Adame Remi Dulize Dariusz Peric Catherine Nury James Battey Emmanuel Guedj Nicolas Sierro Damian Mc Hugh Edward Rockenstein Changyoun Kim Robert A. Rissman Julia Hoeng Manuel C. Peitsch Eliezer Masliah Carole Mathis |
| author_facet | Mohamed Bilal Fares Omar Alijevic Stephanie Johne Cassia Overk Makoto Hashimoto Athanasios Kondylis Anthony Adame Remi Dulize Dariusz Peric Catherine Nury James Battey Emmanuel Guedj Nicolas Sierro Damian Mc Hugh Edward Rockenstein Changyoun Kim Robert A. Rissman Julia Hoeng Manuel C. Peitsch Eliezer Masliah Carole Mathis |
| author_sort | Mohamed Bilal Fares |
| collection | DOAJ |
| description | IntroductionAlpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson’s disease. The plant alkaloid “nicotine” was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear.MethodsIn this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action.Results and discussionOverall, our results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine’s neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects. |
| format | Article |
| id | doaj-art-eae8ebe4bbe94ac488d6544ea8c9efeb |
| institution | Kabale University |
| issn | 1662-453X |
| language | English |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj-art-eae8ebe4bbe94ac488d6544ea8c9efeb2025-08-20T03:34:14ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2023-08-011710.3389/fnins.2023.12390091239009Nicotine-mediated effects in neuronal and mouse models of synucleinopathyMohamed Bilal Fares0Omar Alijevic1Stephanie Johne2Cassia Overk3Makoto Hashimoto4Athanasios Kondylis5Anthony Adame6Remi Dulize7Dariusz Peric8Catherine Nury9James Battey10Emmanuel Guedj11Nicolas Sierro12Damian Mc Hugh13Edward Rockenstein14Changyoun Kim15Robert A. Rissman16Julia Hoeng17Manuel C. Peitsch18Eliezer Masliah19Carole Mathis20PMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandDepartment of Neurosciences, University of California, San Diego, San Diego, CA, United StatesPMI R&D, Philip Morris Products S.A., Neuchâtel, SwitzerlandIntroductionAlpha-synuclein (α-Syn) aggregation, transmission, and contribution to neurotoxicity represent central mechanisms underlying Parkinson’s disease. The plant alkaloid “nicotine” was reported to attenuate α-Syn aggregation in different models, but its precise mode of action remains unclear.MethodsIn this study, we investigated the effect of 2-week chronic nicotine treatment on α-Syn aggregation, neuroinflammation, neurodegeneration, and motor deficits in D-line α-Syn transgenic mice. We also established a novel humanized neuronal model of α-Syn aggregation and toxicity based on treatment of dopaminergic neurons derived from human induced pluripotent stem cells (iPSC) with α-Syn preformed fibrils (PFF) and applied this model to investigate the effects of nicotine and other compounds and their modes of action.Results and discussionOverall, our results showed that nicotine attenuated α-Syn-provoked neuropathology in both models. Moreover, when investigating the role of nicotinic acetylcholine receptor (nAChR) signaling in nicotine’s neuroprotective effects in iPSC-derived dopaminergic neurons, we observed that while α4-specific antagonists reduced the nicotine-induced calcium response, α4 agonists (e.g., AZD1446 and anatabine) mediated similar neuroprotective responses against α-Syn PFF-provoked neurodegeneration. Our results show that nicotine attenuates α-Syn-provoked neuropathology in vivo and in a humanized neuronal model of synucleinopathy and that activation of α4β2 nicotinic receptors might mediate these neuroprotective effects.https://www.frontiersin.org/articles/10.3389/fnins.2023.1239009/fullsynucleinopathyinduced pluripotent stem cell (iPSC)transgenic micenicotinenicotinic acetylcholine receptors (nAChR)neuroprotection |
| spellingShingle | Mohamed Bilal Fares Omar Alijevic Stephanie Johne Cassia Overk Makoto Hashimoto Athanasios Kondylis Anthony Adame Remi Dulize Dariusz Peric Catherine Nury James Battey Emmanuel Guedj Nicolas Sierro Damian Mc Hugh Edward Rockenstein Changyoun Kim Robert A. Rissman Julia Hoeng Manuel C. Peitsch Eliezer Masliah Carole Mathis Nicotine-mediated effects in neuronal and mouse models of synucleinopathy Frontiers in Neuroscience synucleinopathy induced pluripotent stem cell (iPSC) transgenic mice nicotine nicotinic acetylcholine receptors (nAChR) neuroprotection |
| title | Nicotine-mediated effects in neuronal and mouse models of synucleinopathy |
| title_full | Nicotine-mediated effects in neuronal and mouse models of synucleinopathy |
| title_fullStr | Nicotine-mediated effects in neuronal and mouse models of synucleinopathy |
| title_full_unstemmed | Nicotine-mediated effects in neuronal and mouse models of synucleinopathy |
| title_short | Nicotine-mediated effects in neuronal and mouse models of synucleinopathy |
| title_sort | nicotine mediated effects in neuronal and mouse models of synucleinopathy |
| topic | synucleinopathy induced pluripotent stem cell (iPSC) transgenic mice nicotine nicotinic acetylcholine receptors (nAChR) neuroprotection |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2023.1239009/full |
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