Year: 2019
Type: article
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 Ca 2+ 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 Ca 2+ signals and Ca 2+ -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 Ca 2+ -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 Ca 2+ -dependent neurodegeneration in Parkinson’s disease.
Source: Nature Communications
Authors: 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, Birgit Liss
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,505
Awards: G1207168825, UK Dementias Platform, Membrane contact sites between endolysosomes and the ER as novel hubs in Ca2+ signalling., G1595590610, G1849884957, G2456406778, G346694023, G3787271969, UKDP: Integrated DEmentiA research environment (IDEA), G4397111046, G4653495942, G54595414, UKDP: Integrated DEmentiA research environment (IDEA), G7289609437, Cav1.3 L-type calcium channel dysfunction in human disease, G833416507
OpenAlex ID: W2986109479