α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability
Abstract 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 o...
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Nature Portfolio
2021
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oai:doaj.org-article:f2d73277ffa44878aef6f4a90d2e0da92021-12-02T15:10:40Zα-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability10.1038/s41531-021-00210-w2373-8057https://doaj.org/article/f2d73277ffa44878aef6f4a90d2e0da92021-08-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00210-whttps://doaj.org/toc/2373-8057Abstract 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.Abeer DagraDouglas R. MillerMin LinAdithya GopinathFatemeh ShaerzadehSharonda HarrisZachary A. SorrentinoJonatan Fullerton StøierSophia VelascoJanelle AzarAdetola R. AlongeJoseph J. LebowitzBrittany UlmMengfei BuCarissa A. HansenNikhil UrsBenoit I. GiassonHabibeh KhoshboueiNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-22 (2021) |
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Neurology. Diseases of the nervous system RC346-429 |
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Neurology. Diseases of the nervous system RC346-429 Abeer Dagra Douglas R. Miller Min Lin Adithya Gopinath Fatemeh Shaerzadeh Sharonda Harris Zachary A. Sorrentino Jonatan Fullerton Støier Sophia Velasco Janelle Azar Adetola R. Alonge Joseph J. Lebowitz Brittany Ulm Mengfei Bu Carissa A. Hansen Nikhil Urs Benoit I. Giasson Habibeh Khoshbouei α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability |
| description |
Abstract 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. |
| format |
article |
| author |
Abeer Dagra Douglas R. Miller Min Lin Adithya Gopinath Fatemeh Shaerzadeh Sharonda Harris Zachary A. Sorrentino Jonatan Fullerton Støier Sophia Velasco Janelle Azar Adetola R. Alonge Joseph J. Lebowitz Brittany Ulm Mengfei Bu Carissa A. Hansen Nikhil Urs Benoit I. Giasson Habibeh Khoshbouei |
| author_facet |
Abeer Dagra Douglas R. Miller Min Lin Adithya Gopinath Fatemeh Shaerzadeh Sharonda Harris Zachary A. Sorrentino Jonatan Fullerton Støier Sophia Velasco Janelle Azar Adetola R. Alonge Joseph J. Lebowitz Brittany Ulm Mengfei Bu Carissa A. Hansen Nikhil Urs Benoit I. Giasson Habibeh Khoshbouei |
| author_sort |
Abeer Dagra |
| title |
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_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_sort |
α-synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/f2d73277ffa44878aef6f4a90d2e0da9 |
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