Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici syndrome patients

Abstract

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, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and autophagic clearance. Here, we used Drosophila melanogaster to study the importance of Epg5 in development, aging, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions. Abbreviations: AD: Alzheimer's disease; ALS-FTD: Amyotrophic Lateral Sclerosis-FrontoTemoporal Dementia; DART: Drosophila Arousal Tracking; ECoG: electrocorticogram; EEG: electroencephalogram; EPG5: ectopic P-granules 5 autophagy tethering factor; KA: kainic acid; MBs: mushroom bodies; MRI magnetic resonance imaging; MTOR: mechanistic target of rapamycin kinase; PD: Parkinson's disease; TSC: TSC complex; VS: Vici syndrome.