Adapting the endoplasmic reticulum proteostasis rescues epilepsy-associated NMDA receptor variants  

作　　者：Pei-pei Zhang Taylor M.Benske Lucie Y.Ahn Ashleigh E.Schaffer James C.Paton Adrienne W.Paton Ting-wei Mu Ya-juan Wang 

机构地区：[1]Department of Physiology and Biophysics,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA [2]Department of Genetics and Genome Sciences,Case Western Reserve University School of Medicine,Cleveland,OH 44106,USA [3]Research Centre for Infectious Diseases,Department of Molecular and Biomedical Science,University of Adelaide,Adelaide,SA 5005,Australia

出　　处：《Acta Pharmacologica Sinica》2024年第2期282-297,共16页中国药理学报（英文版）

基　　金：supported by the National Institutes of Health(R01NS117176 to TWM,R01NS123524 to AES,and F30HD110088 to LYA);the Brain Research Foundation(BRFSG-2021-08 to AES).

摘　　要：The GRIN genes encoding N-methyl-D-aspartate receptor(NMDAR)subunits are remarkably intolerant to variation.Many pathogenic NMDAR variants result in their protein misfolding,inefficient assembly,reduced surface expression,and impaired function on neuronal membrane,causing neurological disorders including epilepsy and intellectual disability.Here,we investigated the proteostasis maintenance of NMDARs containing epilepsy-associated variations in the GluN2A subunit,including M705V and A727T.In the transfected HEK293T cells,we showed that the two variants were targeted to the proteasome for degradation and had reduced functional surface expression.We demonstrated that the application of BIX,a known small molecule activator of an HSP70 family chaperone BiP(binding immunoglobulin protein)in the endoplasmic reticulum(ER),dose-dependently enhanced the functional surface expression of the M705V and A727T variants in HEK293T cells.Moreover,BIX(10μM)increased the surface protein levels of the M705V variant in human iPSC-derived neurons.We revealed that BIX promoted folding,inhibited degradation,and enhanced anterograde trafficking of the M705V variant by modest activation of the IRE1 pathway of the unfolded protein response.Our results suggest that adapting the ER proteostasis network restores the folding,trafficking,and function of pathogenic NMDAR variants,representing a potential treatment for neurological disorders resulting from NMDAR dysfunction.

关 键 词：NMDA receptors endoplasmic reticulum unfolded protein response PROTEOSTASIS EPILEPSY CHANNELOPATHY 

分 类 号：R742.1[医药卫生—神经病学与精神病学]