Figure 4.

A role for intracellular PrP retention in NMDAR dysfunction. (a) PrP^C on the plasma membrane (PM) attenuates NMDAR activity by associating with the NR2D subunit. (b) Owing to PrP^C misfolding in transport organelles (ER/Golgi), PrP^C is retained intracellularly. This results in increased NMDAR activation, potentially triggering neurotoxicity. (c) Intracellular retention of misfolded PrP^C with NR2D and NR1 subunits results in impaired delivery of NMDARs to the cell surface or their abnormal targeting to extrasynaptic sites, leading to loss of NMDAR function and/or activation of neurotoxic stimuli.