Although it is well established that misfolding of the cellular prion protein (PrP C ) into the β-sheet-rich, aggregated scrapie conformation (PrP Sc ) causes a variety of transmissible spongiform encephalopathies (TSEs), the physiological roles of PrP C are still incompletely understood. There is accumulating evidence describing the roles of PrP C in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrP C that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca 2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrP C play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrP Sc -induced neuronal death. Moreover, in mice lacking PrP C , infarct size is increased after focal cerebral ischemia, and absence of PrP C increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrP C was found to be a receptor for oligomeric beta-amyloid (Aβ) peptides, suggesting a role for PrP C in Alzheimer's disease (AD). Our recent findings suggest that Aβ peptides enhance NMDA receptor current by perturbing the normal copper- and PrP C -dependent regulation of these receptors. Here, we review evidence highlighting a role for PrP C in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrP C -mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrP C -mediated regulation and identifying PrP C binding site(s) on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for AD and other neurodegenerative disorders involving dysfunction of PrP C .
CITATION STYLE
Black, S. A. G., Stys, P. K., Zamponi, G. W., & Tsutsui, S. (2014, August 28). Cellular prion protein and NMDA receptor modulation: Protecting against excitotoxicity. Frontiers in Cell and Developmental Biology. Frontiers Media S.A. https://doi.org/10.3389/fcell.2014.00045
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