Epg5 Links Proteotoxic Stress Due to Defective Autophagic Clearance and Epileptogenesis in Drosophila and Vici Syndrome Patients

Background/Purpose: Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism that has been linked to epileptogenesis when impaired. The precise molecular mechanisms underlying this association remain uncertain. Vici Syndrome is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the EPG5 gene, encoding ectopic P-granules autophagy tethering factor 5, with a crucial role in effective autophagic clearance. Vici syndrome is characterized by a wide range of neurodevelopmental, neurodegenerative, and neurological features, including epilepsy. The role of neuronal loss in epileptogenesis in Vici syndrome remains unclear to this date.