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

Benkert J., Hess S., Roy S., Beccano-Kelly D., Wiederspohn N., Duda J., Simons C., Patil K., Gaifullina A., Mannal N., Dragicevic E., Spaich D., Müller S., Nemeth J., Hollmann H., Deuter N., Mousba Y., Kubisch C., Poetschke C., Striessnig J., Pongs O., Schneider T., Wade-Martins R., Patel S., Parlato R., Frank T., Kloppenburg P., Liss B.

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.

DOI

10.1038/s41467-019-12834-x

Type

Journal article

Journal

Nat Commun

Publication Date

08/11/2019

Volume

10

Keywords

Aging, Animals, Calcium Channels, R-Type, Calcium Signaling, Cation Transport Proteins, Cell Survival, Dopaminergic Neurons, Humans, Induced Pluripotent Stem Cells, Mice, Mice, Knockout, Neuronal Calcium-Sensor Proteins, Neuropeptides, Parkinson Disease, Substantia Nigra, Up-Regulation, Ventral Tegmental Area

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