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

Julia Benkert, Simon Hess, Shoumik Roy, Dayne Beccano-Kelly, Nicole Wiederspohn, Johanna Duda, Carsten Simons, Komal Patil, Aisylu Gaifullina, Nadja Mannal, Elena Dragicevic, Desirée Spaich, Sonja Müller, Julia Nemeth, Helene Hollmann, Nora Deuter, Yassine Mousba, Christian Kubisch, Christina Poetschke, Joerg Striessnig, Olaf Pongs, Toni Schneider, Richard Wade-Martins, Sandip Patel, Rosanna Parlato, Tobias Frank, Peter Kloppenburg and Birgit Liss ()
Additional contact information
Julia Benkert: University of Ulm
Simon Hess: University of Cologne
Shoumik Roy: University of Ulm
Dayne Beccano-Kelly: University of Oxford
Nicole Wiederspohn: University of Ulm
Johanna Duda: University of Ulm
Carsten Simons: University of Ulm
Komal Patil: University of Ulm
Aisylu Gaifullina: University of Ulm
Nadja Mannal: University of Ulm
Elena Dragicevic: University of Ulm
Desirée Spaich: University of Ulm
Sonja Müller: University of Ulm
Julia Nemeth: University of Ulm
Helene Hollmann: University of Ulm
Nora Deuter: University of Ulm
Yassine Mousba: University of Oxford
Christian Kubisch: University Medical Center Hamburg-Eppendorf
Christina Poetschke: University of Ulm
Joerg Striessnig: University of Innsbruck
Olaf Pongs: University of the Saarland
Toni Schneider: University of Cologne
Richard Wade-Martins: University of Oxford
Sandip Patel: Department of Cell and Developmental Biology, UCL
Rosanna Parlato: University of Ulm
Tobias Frank: University Medicine Göttingen
Peter Kloppenburg: University of Cologne
Birgit Liss: University of Ulm

Nature Communications, 2019, vol. 10, issue 1, 1-11

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.

Date: 2019
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DOI: 10.1038/s41467-019-12834-x

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