# A GluN2B disease-associated variant promotes the degradation of NMDA receptors via autophagy

## TL;DR

A disease-linked variant of GluN2B causes NMDA receptor degradation through autophagy, offering new insights into neurological disorders.

## Contribution

The study reveals a novel molecular mechanism for ER-to-lysosome degradation of NMDAR variants involving autophagy and the LIR motif.

## Key findings

- The R519Q GluN2B variant is retained in the ER and degraded via the autophagy-lysosomal pathway.
- The LIR motif in GluN2B facilitates autophagic clearance of the variant.
- The ER-phagy receptor CCPG1 recognizes the variant, and the LIR domain enhances this interaction.

## Abstract

N-methyl-D-aspartate receptors (NMDARs) are essential for excitatory neurotransmission, and missense mutations can severely disrupt their function. Pathogenic variants often lead to proteostasis defects, including improper folding, impaired assembly, and reduced trafficking to the plasma membrane, ultimately compromising the physiological function of NMDARs and thereby contributing to neurological diseases. However, mechanisms by which the proteostasis network recognizes and degrades aggregated, misfolded, and trafficking-deficient pathogenic NMDARs remain poorly understood. Here, we demonstrate that the R519Q GluN2B variant is retained in the endoplasmic reticulum (ER) and fails to traffic to the cell surface to form functional NMDARs. Pharmacological and genetic inhibition of autophagy resulted in the accumulation of this variant, indicating that it is degraded by the autophagy-lysosomal proteolysis pathway. Since the GluN2B subunit has a cytosolic LC3-interacting region (LIR) motif, disruption of the LIR motif via mutagenesis similarly impairs the autophagic clearance of this variant. Furthermore, we demonstrate that this variant is recognized by the ER-phagy receptor CCPG1 and that the LIR domain plays a facilitative role in strengthening this interaction. Our results provide a novel molecular mechanism for the ER-to-lysosome-associated degradation of NMDAR variants and identify a pathway for targeted therapeutic intervention for neurological disorders with dysfunctional NMDARs.