MassIVE MSV000094427

Partial Public PXD051060

Dysregulated Prion signaling induces calcium influx, protein kinase C activation, and NMDA receptor dependent excitotoxicity

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Description

Neuronal hyperexcitability precedes synapse loss in certain neurodegenerative diseases, yet the synaptic membrane interactions and downstream signaling events remain unclear. The disordered amino terminus of the prion protein (PrPC) has been implicated in aberrant signaling in prion and Alzheimer’s disease. To disrupt neuronal interactions and signaling linked to the amino terminus, we CRISPR-engineered a knockin mouse expressing mutant PrPC (G92N), generating an N-linked glycosylation site between 2 functional motifs. Mice developed seizures and necrosis of hippocampal pyramidal neurons, similar to prion-infected mice and consistent with excitotoxicity. Phosphoproteomics analysis revealed phosphorylated glutamate receptors and calcium-sensitive kinases, including protein kinase C (PKC). Additionally, 92N-PrPC-expressing neurons showed persistent calcium influx as well as dendritic beading, which was rescued by an N-methyl-d-aspartate receptor (NMDAR) antagonist. Finally, survival of Prnp92N mice was prolonged by blocking active NMDAR channels. We propose that dysregulated PrPC/NMDAR-induced signaling can trigger an excitatory, inhibitory imbalance, spongiform degeneration, and neurotoxicity and that calcium dysregulation is central to PrPC-linked neurodegeneration. [doi:10.25345/C57D2QJ89] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: glycans ; neuron

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Principal Investigators:
(in alphabetical order) 		Christina Sigurdson, UC San Diego, USA
Submitting User: dmcclat
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