Dysfunctional endocytosis in epilepsy.

In this proposal I aim to take advantage of epileptic encephalopathies (EE) as a genetic model to unravel and subsequently to functionally investigate uncharacterized proteins of the synaptic vesicle endocytosis (SVE) pathway. Mutations in genes leading to the dysregulation of SVE were recently shown to cause EE. Via whole exome sequencing we identified variants of unknownsignificance in six genes likely to be involved in SVE based on indirect evidence (e.g. the protein product (1) contains domains known to be functional in SVE or (2) is involved in endocytosis, but the role in SVE is unknown). I will perform a mutation analysis of these genes in 500 EE patients by gene panel analysis, allowing me to identify mutations in multiple unrelated patients providing the necessary genetic evidence to determine causality. For causative genes identified by this approach, I hypothesize that the inappropriate neuronal firing/seizures may be due to abnormalities in the regulation of synaptic transmission. Furthermore, I will investigate the functionality of one of the already identified causative genes in vivo by creating transgenic fruit flies modelling genes deficiency using state-of-the-art methodologies and analyse these mutants using complementarytechniques, including electrophysiology, live imaging and electron microscopy. Not only will these findings be of importance for understanding the pathophysiology of EE, but they will also further unravel the cell biology of SVE.

Keywords:GENETIC DISEASE, EPILEPSY

Disciplines:Scientific computing, Bioinformatics and computational biology, Public health care, Public health services

Project type:Collaboration project