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In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition
Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contr...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185945/ https://www.ncbi.nlm.nih.gov/pubmed/34099060 http://dx.doi.org/10.1186/s40478-021-01203-9 |
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author | Lin, Min Mackie, Phillip M. Shaerzadeh, Fatima Gamble-George, Joyonna Miller, Douglas R. Martyniuk, Chris J. Khoshbouei, Habibeh |
author_facet | Lin, Min Mackie, Phillip M. Shaerzadeh, Fatima Gamble-George, Joyonna Miller, Douglas R. Martyniuk, Chris J. Khoshbouei, Habibeh |
author_sort | Lin, Min |
collection | PubMed |
description | Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contributes to dopaminergic neuron vulnerability remain unknown. The inaccessibility to diseased tissue has been a limitation in studying progression of pathophysiology prior to degeneration of dopamine neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from a PD patient carrying the α-synuclein triplication mutation (AST) and an unaffected first-degree relative (NAS) into dopaminergic neurons. In human-like dopamine neurons α-synuclein overexpression reduced the functional availability of D2 receptors, resulting in a stark dysregulation in firing activity, dopamine release, and neuronal morphology. We back-translated these findings into primary mouse neurons overexpressing α-synuclein and found a similar phenotype, supporting the causal role for α-synuclein. Importantly, application of D2 receptor agonist, quinpirole, restored the altered firing activity of AST-derived dopaminergic neurons to normal levels. These results provide novel insights into the pre-degenerative pathophysiological neuro-phenotype induced by α-synuclein overexpression and introduce a potential mechanism for the long-established clinical efficacy of D2 receptor agonists in the treatment of PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01203-9. |
format | Online Article Text |
id | pubmed-8185945 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-81859452021-06-09 In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition Lin, Min Mackie, Phillip M. Shaerzadeh, Fatima Gamble-George, Joyonna Miller, Douglas R. Martyniuk, Chris J. Khoshbouei, Habibeh Acta Neuropathol Commun Research Pathophysiological changes in dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease (PD). Intracellular pathological inclusions of the protein α-synuclein within dopaminergic neurons are a cardinal feature of PD, but the mechanisms by which α-synuclein contributes to dopaminergic neuron vulnerability remain unknown. The inaccessibility to diseased tissue has been a limitation in studying progression of pathophysiology prior to degeneration of dopamine neurons. To address these issues, we differentiated induced pluripotent stem cells (iPSCs) from a PD patient carrying the α-synuclein triplication mutation (AST) and an unaffected first-degree relative (NAS) into dopaminergic neurons. In human-like dopamine neurons α-synuclein overexpression reduced the functional availability of D2 receptors, resulting in a stark dysregulation in firing activity, dopamine release, and neuronal morphology. We back-translated these findings into primary mouse neurons overexpressing α-synuclein and found a similar phenotype, supporting the causal role for α-synuclein. Importantly, application of D2 receptor agonist, quinpirole, restored the altered firing activity of AST-derived dopaminergic neurons to normal levels. These results provide novel insights into the pre-degenerative pathophysiological neuro-phenotype induced by α-synuclein overexpression and introduce a potential mechanism for the long-established clinical efficacy of D2 receptor agonists in the treatment of PD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01203-9. BioMed Central 2021-06-07 /pmc/articles/PMC8185945/ /pubmed/34099060 http://dx.doi.org/10.1186/s40478-021-01203-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lin, Min Mackie, Phillip M. Shaerzadeh, Fatima Gamble-George, Joyonna Miller, Douglas R. Martyniuk, Chris J. Khoshbouei, Habibeh In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title | In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title_full | In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title_fullStr | In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title_full_unstemmed | In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title_short | In Parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding D2 receptor autoinhibition |
title_sort | in parkinson's patient-derived dopamine neurons, the triplication of α-synuclein locus induces distinctive firing pattern by impeding d2 receptor autoinhibition |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185945/ https://www.ncbi.nlm.nih.gov/pubmed/34099060 http://dx.doi.org/10.1186/s40478-021-01203-9 |
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