Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson's disease
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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.
In: NAT COMMUN, Vol. 10, No. 1, 08.11.2019, p. 5094.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson's disease
AU - Benkert, Julia
AU - Hess, Simon
AU - Roy, Shoumik
AU - Beccano-Kelly, Dayne
AU - Wiederspohn, Nicole
AU - Duda, Johanna
AU - Simons, Carsten
AU - Patil, Komal
AU - Gaifullina, Aisylu
AU - Mannal, Nadja
AU - Dragicevic, Elena
AU - Spaich, Desirée
AU - Müller, Sonja
AU - Nemeth, Julia
AU - Hollmann, Helene
AU - Deuter, Nora
AU - Mousba, Yassine
AU - Kubisch, Christian
AU - Poetschke, Christina
AU - Striessnig, Joerg
AU - Pongs, Olaf
AU - Schneider, Toni
AU - Wade-Martins, Richard
AU - Patel, Sandip
AU - Parlato, Rosanna
AU - Frank, Tobias
AU - Kloppenburg, Peter
AU - Liss, Birgit
PY - 2019/11/8
Y1 - 2019/11/8
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-12834-x
DO - 10.1038/s41467-019-12834-x
M3 - SCORING: Journal article
C2 - 31704946
VL - 10
SP - 5094
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -