• Lafora disease
• progressive myoclonic epilepsies
• epm2a
• zebrafish epilepsy model
• autophagy
• trehalose.

Background: Mutations in the EPM2A gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant epilepsy and progressive neurological damage. To date, rodents are the only models available to study LD. However, the high cost of reproduction and regulatory limitations reduce their use in drug screening. In contrast, zebrafish represent a successful model for the study of neurodevelopmental and neurodegenerative disorders and for drug screening.

Aims and Methods: We developed and characterized a loss of function model of laforin in zebrafish to understand the role of protein in early neurodevelopment and to gather a new tool for drug screening.

Results: We showed that epm2a-/- zebrafish is a faithful model of LD, showing the main phenotypic features of LD, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. In addition, we revealed an enhanced inflammatory response and apoptotic death and an altered autophagy pathway, which occurs early in development and likely contributes to disease progression. We also demonstrated that early administration of trehalose is sufficient to rescue motor disability and spontaneous seizures in zebrafish mutant larvae.

Conclusions: Laforin-deficient zebrafish represent a valuable tool to study Lafora disease and provide a unique platform for studying the early stages of the disease and drug screening. The possibility to study early steps in developing LD gave us also the opportunity to discuss on the role of Lafora bodies, supporting the notion that they are not the only responsible for LD.