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Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 trans...

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Autores principales: Benkert, Julia, Hess, Simon, Roy, Shoumik, Beccano-Kelly, Dayne, Wiederspohn, Nicole, Duda, Johanna, Simons, Carsten, Patil, Komal, Gaifullina, Aisylu, Mannal, Nadja, Dragicevic, Elena, Spaich, Desirée, Müller, Sonja, Nemeth, Julia, Hollmann, Helene, Deuter, Nora, Mousba, Yassine, Kubisch, Christian, Poetschke, Christina, Striessnig, Joerg, Pongs, Olaf, Schneider, Toni, Wade-Martins, Richard, Patel, Sandip, Parlato, Rosanna, Frank, Tobias, Kloppenburg, Peter, Liss, Birgit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841684/
https://www.ncbi.nlm.nih.gov/pubmed/31704946
http://dx.doi.org/10.1038/s41467-019-12834-x
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author Benkert, Julia
Hess, Simon
Roy, Shoumik
Beccano-Kelly, Dayne
Wiederspohn, Nicole
Duda, Johanna
Simons, Carsten
Patil, Komal
Gaifullina, Aisylu
Mannal, Nadja
Dragicevic, Elena
Spaich, Desirée
Müller, Sonja
Nemeth, Julia
Hollmann, Helene
Deuter, Nora
Mousba, Yassine
Kubisch, Christian
Poetschke, Christina
Striessnig, Joerg
Pongs, Olaf
Schneider, Toni
Wade-Martins, Richard
Patel, Sandip
Parlato, Rosanna
Frank, Tobias
Kloppenburg, Peter
Liss, Birgit
author_facet Benkert, Julia
Hess, Simon
Roy, Shoumik
Beccano-Kelly, Dayne
Wiederspohn, Nicole
Duda, Johanna
Simons, Carsten
Patil, Komal
Gaifullina, Aisylu
Mannal, Nadja
Dragicevic, Elena
Spaich, Desirée
Müller, Sonja
Nemeth, Julia
Hollmann, Helene
Deuter, Nora
Mousba, Yassine
Kubisch, Christian
Poetschke, Christina
Striessnig, Joerg
Pongs, Olaf
Schneider, Toni
Wade-Martins, Richard
Patel, Sandip
Parlato, Rosanna
Frank, Tobias
Kloppenburg, Peter
Liss, Birgit
author_sort Benkert, Julia
collection PubMed
description Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca(2+) channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca(2+) signals and Ca(2+)-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca(2+)-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca(2+)-dependent neurodegeneration in Parkinson’s disease.
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spelling pubmed-68416842019-11-13 Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease Benkert, Julia Hess, Simon Roy, Shoumik Beccano-Kelly, Dayne Wiederspohn, Nicole Duda, Johanna Simons, Carsten Patil, Komal Gaifullina, Aisylu Mannal, Nadja Dragicevic, Elena Spaich, Desirée Müller, Sonja Nemeth, Julia Hollmann, Helene Deuter, Nora Mousba, Yassine Kubisch, Christian Poetschke, Christina Striessnig, Joerg Pongs, Olaf Schneider, Toni Wade-Martins, Richard Patel, Sandip Parlato, Rosanna Frank, Tobias Kloppenburg, Peter Liss, Birgit Nat Commun Article Degeneration of dopaminergic neurons in the substantia nigra causes the motor symptoms of Parkinson’s disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators of nigral neuronal viability. Cav2.3 transcripts were more abundant than other voltage-gated Ca(2+) channels in mouse nigral neurons and upregulated during aging. Plasmalemmal Cav2.3 protein was higher than in dopaminergic neurons of the ventral tegmental area, which do not degenerate in Parkinson’s disease. Cav2.3 knockout reduced activity-associated nigral somatic Ca(2+) signals and Ca(2+)-dependent after-hyperpolarizations, and afforded full protection from degeneration in vivo in a neurotoxin Parkinson’s mouse model. Cav2.3 deficiency upregulated transcripts for NCS-1, a Ca(2+)-binding protein implicated in neuroprotection. Conversely, NCS-1 knockout exacerbated nigral neurodegeneration and downregulated Cav2.3. Moreover, NCS-1 levels were reduced in a human iPSC-model of familial Parkinson’s. Thus, Cav2.3 and NCS-1 may constitute potential therapeutic targets for combatting Ca(2+)-dependent neurodegeneration in Parkinson’s disease. Nature Publishing Group UK 2019-11-08 /pmc/articles/PMC6841684/ /pubmed/31704946 http://dx.doi.org/10.1038/s41467-019-12834-x Text en © The Author(s) 2019 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/.
spellingShingle Article
Benkert, Julia
Hess, Simon
Roy, Shoumik
Beccano-Kelly, Dayne
Wiederspohn, Nicole
Duda, Johanna
Simons, Carsten
Patil, Komal
Gaifullina, Aisylu
Mannal, Nadja
Dragicevic, Elena
Spaich, Desirée
Müller, Sonja
Nemeth, Julia
Hollmann, Helene
Deuter, Nora
Mousba, Yassine
Kubisch, Christian
Poetschke, Christina
Striessnig, Joerg
Pongs, Olaf
Schneider, Toni
Wade-Martins, Richard
Patel, Sandip
Parlato, Rosanna
Frank, Tobias
Kloppenburg, Peter
Liss, Birgit
Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title_full Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title_fullStr Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title_full_unstemmed Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title_short Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
title_sort cav2.3 channels contribute to dopaminergic neuron loss in a model of parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841684/
https://www.ncbi.nlm.nih.gov/pubmed/31704946
http://dx.doi.org/10.1038/s41467-019-12834-x
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