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

Author

Listed:
  • 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
    University of Oxford)

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.

Suggested Citation

  • 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, 2019. "Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12834-x
    DOI: 10.1038/s41467-019-12834-x
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    Cited by:

    1. Yiwei Gao & Shuai Xu & Xiaoli Cui & Hao Xu & Yunlong Qiu & Yiqing Wei & Yanli Dong & Boling Zhu & Chao Peng & Shiqi Liu & Xuejun Cai Zhang & Jianyuan Sun & Zhuo Huang & Yan Zhao, 2023. "Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xia Yao & Yan Wang & Zhifei Wang & Xiao Fan & Di Wu & Jian Huang & Alexander Mueller & Sarah Gao & Miaohui Hu & Carol V. Robinson & Yong Yu & Shuai Gao & Nieng Yan, 2022. "Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Marisol Sampedro-Castañeda & Lucas L. Baltussen & André T. Lopes & Yichen Qiu & Liina Sirvio & Simeon R. Mihaylov & Suzanne Claxton & Jill C. Richardson & Gabriele Lignani & Sila K. Ultanir, 2023. "Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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