MINI REVIEW article
Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
ENDOPLASMIC RETICULUM PROTEIN RETENTION AND DISTURBED PROTEOSTASIS IS A COMMON PATHOLOGY FOR A SUBSET OF AUTISM: EVIDENCE FROM MUTATIONS IN GABAA RECEPTORS AND GABA TRANSPORTER 1
Provisionally accepted
Jing-Qiong Kang1,2,3,4*
Aiden Delahanty4- 1Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, United States
- 2Vanderbilt University Medical Center Vanderbilt O'Brien Kidney Center, Nashville, United States
- 3Vanderbilt University Vanderbilt Brain Institute, Nashville, United States
- 4Vanderbilt University Medical Center, Nashville, United States
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ABSTRACT (<250) Autism is a common childhood disorder, often comorbid with epilepsy. Both autism and epilepsy are highly heterogeneous in terms of disease etiology and frequently co-occur with other neuropsychiatric phenotypes. Advances in genetic sequencing technologies have significantly improved our understanding of the biological pathways involved in these disorders, particularly in genetic epilepsy (GE). One critical pathway involves gamma-aminobutyric acid (GABA), a key neurotrophic signal during early brain development. GABA plays a central role in maintaining neural excitatory-inhibitory balance, and its dysfunction has been implicated in both autism and epilepsy. GABA acts through its receptors and transporters to regulate neuronal signaling, and disruptions in this system can lead to neural circuit abnormalities. Recent studies have identified that mutations in GABAA receptors and the GABA transporter 1(GAT-1) encoding SLC6A1 result in defective protein folding and retention in the endoplasmic reticulum (ER), leading to impaired proteostasis. This common cellular defect has been observed in a subset of patients with autism and epilepsy, suggesting a shared pathogenic mechanism. We propose that ER retention of mutated proteins and impaired trafficking contribute to disease phenotypes associated with monogenic de novo mutations. Consequently, therapeutic strategies aimed at enhancing protein folding and trafficking, such as the use of chemical or pharmacological chaperones like 4-phenylbutyrate, may provide cross-cutting benefits for both disorders. Our hypothesis highlights the potential for a unified therapeutic approach targeting cellular protein homeostasis in genetically defined subsets of autism and epilepsy.
Keywords: Endoplasmic Reticulum, GABAA receptors, GABA transporter 1, proteostasis, autism, Epilepsy
Received: 22 Jul 2025; Accepted: 01 Dec 2025.
Copyright: © 2025 Kang and Delahanty. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jing-Qiong Kang
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