Mechanisms of neuropsychiatric genetic diseases of the SNARE complex: towards therapeutic intervention
Epileptic seizures are important symptoms of several major brain disorders. Ample evidence suggests that synaptic dysfunction is a central aspect of these diseases leading to disturbed excitation/inhibition balance. Despite some mechanistic insight, treatment success is often limited as one third of epilepsy patients do not respond to available drugs. To find more tailor-made solutions for cases in which generic epilepsy treatment is ineffective, we will gain mechanistic insight in the diverse routes that lead from synaptic dysfunction to seizure phenotypes and search for effective therapies. This proposal unites world-leading experts in the genetics of epilepsy, synapse biology, structural biology, and in vivo behavioral screens to characterize the molecular, synaptic and network dysfunctions of epilepsy-causing mutations in key proteins of the synaptic vesicle release machinery, two central components of the SNARE-complex and one co-factor, that lead to a wide spectrum of seizure phenotypes, many of which respond poorly to available antiepileptic drugs, using a concerted approach in rodent and human, patient-own, cellular models (WP1) and provide screening platforms in human neurons and zebrafish to identify novel therapeutic compounds (WP2). Together, these studies will provide a unique insight into the diverse routes from synapse dysfunction to seizure phenotypes and provide important handles for better patient stratification and personalized treatments.
Epilepsy, Stem cells and neural differentiation/cell therapy, Electrophisiological approaches, Behavioural methodologies, (epi)genetic approaches, Stem cells and neural differentiation/cell therapy, omics approaches, SNAREopathy, synaptic dysfunction, in vivo drug screen, in vitro drug screen, NMR
2018 - 2021
Ruud Toonen (Coordinator)
The Netherlands (NWO)