Abstract 1352 The Proteostasis Regulator PC7 promotes the forward trafficking of NMDA receptors containing the pathogenic GluN1_S688Y variant

N-methyl-D-aspartate receptors (NMDARs) are a class of ion channels found in neurons and play a crucial role in learning and memory by helping translate the chemical signal sent across synapses into an electrical one. Variants of this protein caused by genetic mutation can lead to neurological disorders including intellectual disabilities, developmental disorders, and epilepsies. In order to function as an ion channel, NMDARs must be localized to the synaptic surface. Little is known about the proteostasis network that assists in the folding, trafficking, and membrane insertion of this protein and regulates functional NMDAR expression, despite many pathogenic variants exhibiting deficient surface expression. This study aims to characterize the effects of the pathogenic variant GluN1_S688Y, which causes severe developmental issues and cortical atrophy, on the biogenesis of NMDARs by transiently expressing GluN1/GluN2B heterotetramers in a HEK293T cell system. Compared to GluN1_WT, we observed diminished overall and surface expression of GluN1_S688Y, increased degradation, and decreased stability through Western blot analysis. Novel proteostasis regulators were screened for their ability to increase GluN1 surface expression. PC7 increased the forward trafficking and surface expression of GluN1_S688Y. Restoring the surface expression of this pathogenic variant could help ameliorate patient symptom burden. Further analysis seeks to determine what components of the proteostasis network this compound regulates to enhance the forward trafficking of pathogenic NMDARs. These findings could lead to a novel strategy for the treatment of disorders in which NMDARs or other misfolded proteins are dysregulated.