Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease
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Published:2019-11-08
Issue:1
Volume:10
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Benkert Julia, Hess Simon, Roy Shoumik, Beccano-Kelly Dayne, Wiederspohn Nicole, Duda Johanna, Simons CarstenORCID, Patil Komal, Gaifullina Aisylu, Mannal Nadja, Dragicevic Elena, Spaich Desirée, Müller Sonja, Nemeth JuliaORCID, Hollmann Helene, Deuter Nora, Mousba YassineORCID, Kubisch Christian, Poetschke Christina, Striessnig Joerg, Pongs Olaf, Schneider ToniORCID, Wade-Martins Richard, Patel Sandip, Parlato Rosanna, Frank Tobias, Kloppenburg Peter, Liss BirgitORCID
Abstract
Abstract
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 Ca2+ 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 Ca2+ signals and Ca2+-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 Ca2+-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 Ca2+-dependent neurodegeneration in Parkinson’s disease.
Funder
Austrian Science Fund
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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