Importance of Protein Folding in Seizure-Related Disorders

Proper protein folding is crucial for the function of various proteins, including those implicated in neurological conditions such as seizures and autism spectrum disorder. Recent research underscores how mutations in the hGAT1 protein, linked to these disorders, disrupt its proper folding and hinder its transport to the cell membrane where it performs its essential functions.

The human GABA transporter 1 (hGAT1), encoded by the SLC6A1 gene, plays a vital role in enabling brain cells to absorb the inhibitory neurotransmitter GABA from synaptic spaces. Mutations within the SLC6A1 gene can lead to neurodevelopmental disorders when hGAT1 fails to operate correctly or does not reach the cell's surface.

A study conducted by researchers from the Medical University of Vienna identified that 15 specific mutations in the hGAT1 protein adversely affect its functional capabilities. These mutations prevent the protein from folding correctly, leading to its accumulation within the endoplasmic reticulum instead of being transported to the plasma membrane.

The research team concentrated on two notable mutations at the highly conserved glycine position 443, linked to childhood epilepsy: G443D, where glycine is replaced by aspartic acid, and G443V, where glycine is substituted by valine. In laboratory experiments, it was observed that some of the G443D mutant protein could reach the plasma membrane, while the G443V variant remained trapped within the endoplasmic reticulum, rendering both mutants incapable of effectively taking up GABA.

Encouragingly, certain small molecules have been identified that can assist in correcting the folding of these proteins. For instance, glycerol was found to enhance GABA uptake in cells with the G443D mutation, while 4-phenylbutyrate improved GABA uptake in cells harboring the G443V mutation. These small molecules not only facilitated the transport of the mutated proteins to the plasma membrane but also enhanced the function of both mutant and wild-type proteins.

The investigative team further analyzed these mutations in vivo using fruit fly models, which exhibited similar protein localization issues. When subjected to heat stress, these mutant flies displayed seizure-like movements. However, dietary supplementation with 4-phenylbutyrate significantly reduced the frequency of seizures and corrected the localization of G443V mutant proteins in the flies. Glycerol treatment also led to a modest decrease in seizure activity in both types of mutants.

The findings from this study provide critical insights into how GAT-1 mutations may disrupt protein function and trafficking, emphasizing the necessity for a detailed evaluation of individual mutations to understand the diverse symptoms associated with SLC6A1-related disorders. These results pave the way for potential therapeutic strategies targeting the underlying molecular dysfunctions in related neurological conditions.