Improving Proteostasis of Trafficking-Deficient GABA_A Receptor Variants by Activating IRE1.

ABSTRACT: Gamma-aminobutyric acid type A receptors (GABA_ARs) are essential for maintaining the excitation-inhibition balance in the central nervous system. Genetic variations of GABA_ARs result in a variety of neurological disorders, such as epilepsy. A key pathogenic mechanism involves protein misfolding and defective assembly of GABA_ARs in the endoplasmic reticulum (ER), resulting in impaired surface expression and loss of function. Here, we investigated three trafficking-deficient variants of the GABA_AR α1 subunit (GABRA1), including D219N (ClinVar Variation ID: 127232), G251D (Variation ID: 419523), and P260L. We demonstrated that selective pharmacological activation of the IRE1/XBP1s signaling arm of the unfolded protein response using IXA62, IX

SUBMITTER: Fu X 

PROVIDER: S-EPMC12679549 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature