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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the car...

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Autores principales: Dagra, Abeer, Miller, Douglas R., Lin, Min, Gopinath, Adithya, Shaerzadeh, Fatemeh, Harris, Sharonda, Sorrentino, Zachary A., Støier, Jonatan Fullerton, Velasco, Sophia, Azar, Janelle, Alonge, Adetola R., Lebowitz, Joseph J., Ulm, Brittany, Bu, Mengfei, Hansen, Carissa A., Urs, Nikhil, Giasson, Benoit I., Khoshbouei, Habibeh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373893/
https://www.ncbi.nlm.nih.gov/pubmed/34408150
http://dx.doi.org/10.1038/s41531-021-00210-w
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author Dagra, Abeer
Miller, Douglas R.
Lin, Min
Gopinath, Adithya
Shaerzadeh, Fatemeh
Harris, Sharonda
Sorrentino, Zachary A.
Støier, Jonatan Fullerton
Velasco, Sophia
Azar, Janelle
Alonge, Adetola R.
Lebowitz, Joseph J.
Ulm, Brittany
Bu, Mengfei
Hansen, Carissa A.
Urs, Nikhil
Giasson, Benoit I.
Khoshbouei, Habibeh
author_facet Dagra, Abeer
Miller, Douglas R.
Lin, Min
Gopinath, Adithya
Shaerzadeh, Fatemeh
Harris, Sharonda
Sorrentino, Zachary A.
Støier, Jonatan Fullerton
Velasco, Sophia
Azar, Janelle
Alonge, Adetola R.
Lebowitz, Joseph J.
Ulm, Brittany
Bu, Mengfei
Hansen, Carissa A.
Urs, Nikhil
Giasson, Benoit I.
Khoshbouei, Habibeh
author_sort Dagra, Abeer
collection PubMed
description Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.
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spelling pubmed-83738932021-09-02 α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability Dagra, Abeer Miller, Douglas R. Lin, Min Gopinath, Adithya Shaerzadeh, Fatemeh Harris, Sharonda Sorrentino, Zachary A. Støier, Jonatan Fullerton Velasco, Sophia Azar, Janelle Alonge, Adetola R. Lebowitz, Joseph J. Ulm, Brittany Bu, Mengfei Hansen, Carissa A. Urs, Nikhil Giasson, Benoit I. Khoshbouei, Habibeh NPJ Parkinsons Dis Article Pathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications. Nature Publishing Group UK 2021-08-18 /pmc/articles/PMC8373893/ /pubmed/34408150 http://dx.doi.org/10.1038/s41531-021-00210-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Dagra, Abeer
Miller, Douglas R.
Lin, Min
Gopinath, Adithya
Shaerzadeh, Fatemeh
Harris, Sharonda
Sorrentino, Zachary A.
Støier, Jonatan Fullerton
Velasco, Sophia
Azar, Janelle
Alonge, Adetola R.
Lebowitz, Joseph J.
Ulm, Brittany
Bu, Mengfei
Hansen, Carissa A.
Urs, Nikhil
Giasson, Benoit I.
Khoshbouei, Habibeh
α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title_full α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title_fullStr α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title_full_unstemmed α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title_short α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
title_sort α-synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373893/
https://www.ncbi.nlm.nih.gov/pubmed/34408150
http://dx.doi.org/10.1038/s41531-021-00210-w
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