GluA2 palmitoylation by SELENOK modulates AMPAR assembly and synaptic plasticity in Alzheimer's disease.

Abstract

Se is essential for central nervous system function, and its deficiency is strongly associated with cognitive decline, especially in neurodegenerative disorders such as Alzheimer's disease (AD). Although Se exerts its effects through selenoproteins, the molecular basis of its neuroprotective action remains unclear. Among selenoproteins, the endoplasmic reticulum (ER)-resident selenoprotein K (SELENOK) is closely linked to cognitive function and therapeutic potential in AD. Here, we examined how SELENOK regulates synaptic plasticity and contributes to Se-mediated neuroprotection in AD. Using age-gradient SELENOK knockout models and palmitoyl-proteomics, we identified GluA2 (formerly GluR2) as a key downstream target. Mechanistically, SELENOK enhanced the activity of DHHC6, an ER-localized palmitoyltransferase, to promote GluA2 palmitoylation, facilitating its ER retention and efficient assembly of AMPA-type glutamate receptors (AMPARs). Notably, GluA2 palmitoylation was reduced in both AD model mice and postmortem brains of patients with AD. Importantly, neuronal overexpression of SELENOK in the hippocampus restored synaptic plasticity and cognitive function in AD mice. Overall, this study uncovers a novel SELENOK-dependent mechanism regulating AMPAR assembly, offering experimental support for developing Se-based therapeutic strategies for AD.