Benkert, Julia, Hess, Simon, Roy, Shoumik, Beccano-Kelly, Dayne ORCID: 0000-0003-3592-8354, Wiederspohn, Nicole, Duda, Johanna, Simons, Carsten ORCID: 0000-0003-3936-5181, Patil, Komal, Gaifullina, Aisylu, Mannal, Nadja, Dragicevic, Elena, Spaich, Desiree, Mueller, 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 ORCID: 0000-0001-6682-9645, Frank, Tobias, Kloppenburg, Peter and Liss, Birgit (2019). Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson's disease. Nat. Commun., 10. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Benkert, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roy, ShoumikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beccano-Kelly, DayneUNSPECIFIEDorcid.org/0000-0003-3592-8354UNSPECIFIED
Wiederspohn, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duda, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Simons, CarstenUNSPECIFIEDorcid.org/0000-0003-3936-5181UNSPECIFIED
Patil, KomalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaifullina, AisyluUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mannal, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dragicevic, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spaich, DesireeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, SonjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nemeth, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hollmann, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deuter, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mousba, YassineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kubisch, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poetschke, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striessnig, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pongs, OlafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, ToniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wade-Martins, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patel, SandipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parlato, RosannaUNSPECIFIEDorcid.org/0000-0001-6682-9645UNSPECIFIED
Frank, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloppenburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liss, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-127952
DOI: 10.1038/s41467-019-12834-x
Journal or Publication Title: Nat. Commun.
Volume: 10
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MITOCHONDRIAL OXIDANT STRESS; GATED CALCIUM-CHANNELS; SUBSTANTIA-NIGRA; CA2+ CHANNEL; PACEMAKING; VULNERABILITY; DYSFUNCTION; PROGRESSION; MECHANISMS; INHIBITIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12795

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