4-Phenylbutyrate Rescue in GABRA1 Variants Associated with Developmental Epileptic Encephalopathies: from Cell and...

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Developmental and epileptic encephalopathies (DEEs) are severe genetic disorders often caused by mutations in GABA A receptor (GABA _A R) subunits.
• Current treatments for DEEs are limited, despite GABA _A R being a key target for antiseizure medications.

Purpose of the Study:

• To investigate the therapeutic potential of 4-phenyl-butyrate (PBA) in DEEs caused by GABRA1 mutations.
• To evaluate PBA's effect on GABA _A R subunit expression, trafficking, and function in cellular and animal models.

Main Methods:

• Utilized a multidisciplinary approach including in silico modeling, flow cytometry, patch clamp electrophysiology, and biochemical assays.
• Employed differential tagging to distinguish wild-type and mutant alleles in HEK293T cells and Gabra1 ^+/A322D mice.

Main Results:

• GABRA1 variants reduced total and surface expression of the α1 subunit, leading to decreased GABA-evoked currents.
• In silico analysis predicted reduced protein stability for GABRA1 variants.
• PBA treatment increased both total and surface expression of wild-type and variant α1 subunits, enhancing GABA _A R function.
• PBA administration increased GABA _A R expression in the thalamus of Gabra1 ^+/A322D mice.

Conclusions:

• PBA demonstrates significant therapeutic potential for DEEs linked to GABRA1 mutations by restoring GABA _A R expression and function.
• PBA may act by improving proteostasis, enhancing wild-type allele expression, repairing mutant alleles, and reducing ER stress.
• PBA could serve as a common therapeutic agent for various genetic neurological disorders sharing proteostasis defects, including DEEs.