The Critical Role of Proper Protein Folding in Seizure-Related Disorders

Protein folding is a fundamental process crucial for maintaining the correct structure and function of proteins, much like origami requires precise folds to achieve its artful shapes. Recent research emphasizes that proper folding of specific proteins is essential for their role in neural activity, particularly in relation to seizure disorders. Mutations in certain proteins can disrupt their folding, preventing them from reaching the cell surface where they perform their function, which can lead to neurological conditions such as epilepsy and autism spectrum disorder.

A notable example involves the human GABA transporter 1 (hGAT1), encoded by the SLC6A1 gene. This transporter plays a vital role in regulating neurotransmitter levels by reabsorbing GABA—the brain's primary inhibitory neurotransmitter—from synapses. When hGAT1 malfunctions or fails to reach the cell's plasma membrane, GABA uptake diminishes, causing neuronal excitability that can contribute to seizures.

Recent studies have uncovered that various mutations in SLC6A1 impair the folding of hGAT1. Specifically, mutations at the highly conserved glycine at amino acid position 443—namely G443D and G443V—are linked to childhood epilepsy. Laboratory experiments have demonstrated that while some G443D mutant proteins can reach the cell surface, others become trapped inside the cell. Conversely, G443V mutants are predominantly retained within the endoplasmic reticulum, thus failing to perform their GABA reuptake function. This improper localization results in decreased GABA clearance and increased likelihood of seizure activity.

Importantly, scientists have identified that small molecules like glycerol and 4-phenylbutyrate can correct these folding defects, restoring the proteins' ability to reach the cell surface and resume function. In vitro tests have shown these molecules increase GABA uptake in mutant cells. Further in vivo studies using fruit fly models have supported these findings, showing that treatment with these compounds reduces seizure-like behaviors and improves protein localization.

This research highlights the significance of protein folding in neurological health. It suggests that mutation-specific therapies targeting folding defects could offer new treatment avenues for SLC6A1-related epilepsy and related disorders. These findings underscore the importance of understanding individual mutations and developing tailored interventions to restore normal protein function and prevent seizures.

Source: https://medicalxpress.com/news/2025-06-proper-important-protein-seizures.html