Improving Proteostasis of Trafficking-Deficient GABA_AReceptor Variants by Activating IRE1

Authors

• Xu Fu, Case Western Reserve University School of Medicine
• Ya Juan Wang, Case Western Reserve University School of Medicine
• Kyung A. Lee, Scripps Research Institute
• Lucie Y. Ahn, Case Western Reserve University School of Medicine
• Xi Chen, Case Western Reserve University School of Medicine
• Brock T. Harvey, University of KentuckyFollow
• Meng Wang, Case Western Reserve University School of Medicine
• Hailey Seibert, Case Western Reserve University School of Medicine
• Pei Pei Zhang, Case Western Reserve University School of Medicine
• Adrian Guerrero, Scripps Research Institute
• Ashleigh E. Schaffer, Case Western Reserve University School of Medicine
• Christopher I. Richards, University of KentuckyFollow
• R. Luke Wiseman, Scripps Research Institute
• Jeffery W. Kelly, Scripps Research Institute
• Ting Wei Mu, Case Western Reserve University School of MedicineFollow

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, IXA554, and IXA105 increases total and surface protein levels of all three α1 variants without affecting wild-type receptor protein levels in HEK293T cells. Patch-clamping recordings further showed that treatment with IXA62, IXA554, and IXA105 increases the peak GABA-evoked current amplitudes in HEK293T cells expressing α1(D219N) and α1(G251D). Mechanistic analyses revealed that IXA62 and IXA554 remodel the GABA_AR-associated proteostasis network by promoting folding and anterograde trafficking while inhibiting degradation in HEK293T cells expressing α1(D219N) variant and human iPSC-derived neurons carrying α1(G251D) variant. These results suggest that selective IRE1/XBP1s activation pharmacologically can be further developed to provide a potential therapeutic avenue for genetic epilepsies caused by GABA_AR trafficking defects.

Document Type

Article

Publication Date

1-1-2025

Notes/Citation Information

Publisher Copyright: © 2025 The Authors. Published by American Chemical Society

Digital Object Identifier (DOI)

10.1021/acschemneuro.5c00227

Archival?

Archival

Repository Citation

Fu, Xu; Wang, Ya Juan; Lee, Kyung A.; Ahn, Lucie Y.; Chen, Xi; Harvey, Brock T.; Wang, Meng; Seibert, Hailey; Zhang, Pei Pei; Guerrero, Adrian; Schaffer, Ashleigh E.; Richards, Christopher I.; Wiseman, R. Luke; Kelly, Jeffery W.; and Mu, Ting Wei, "Improving Proteostasis of Trafficking-Deficient GABA_AReceptor Variants by Activating IRE1" (2025). Chemistry Faculty Publications. 254.
https://uknowledge.uky.edu/chemistry_facpub/254