| dc.description.abstract | Epilepsy is one of the most common neurological disorders, and current treatments fail to provide seizure control for ~30% of patients. Most pharmacological treatments target ion channels and neurotransmission, yet the number of people still experiencing seizures indicates that other therapeutic approaches are desperately needed. One promising new approach is modulation of proteostasis – the dynamic regulation of protein folding, trafficking, and degradation – and this may be especially useful for genetic epilepsies. Moreso than acquired epilepsies, epilepsies with a genetic etiology often have misfolded, mutant proteins. The epilepsy-causing GABRG2(Q390X) mutation, in particular, codes for the γ2(Q390X) GABAA receptor subunit, and this mutant protein accumulates within the endoplasmic reticulum (ER). Misfolded proteins such as the γ2(Q390X) subunit present a continuous burden to a cell’s proteostasis machinery. My research has aimed to characterize the impairments to protein degradation pathways, autophagy and the ubiquitin-proteasome system (UPS), resulting from the GABRG2(Q390X) mutation. Using heterologous cell models, alterations in expression patterns of the autophagy protein LC3B and increased UPS activity were identified. Additional proteostasis aberrations were detected in Gabrg2+/Q390X mice: an increase in the ER chaperone BiP and a disparate response to a proteostasis regulator compared to wildtype animals. However, overexpression of an ER-associated degradation component, HRD1, was found to decrease expression of the deleterious γ2(Q390X) subunit, suggesting a potential mechanism for new therapeutics. Furthermore, the chemical chaperone 4-phenylbutyrate nearly abolished spontaneous seizures in Gabrg2+/Q390X mice, providing in vivo evidence that modulating proteostasis can treat epilepsy. Thus, the characterization of cellular defects beyond loss of ion channel function, such as protein trafficking and UPS activity, in genetic epilepsies will enable development of novel therapeutics for patients currently lacking adequate care. | |
