Warburg Micro Syndrome (WMS) is a rare, inherited neurological disease with early- onset symptoms including microcephaly, severe developmental delay, and progressive motor dysfunction. Most affected children never walk or speak, and current management is limited to supportive care. No treatments currently exist to address the underlying pathogenic mechanisms of WMS. The most common genetic cause of WMS is loss-of-function mutations in the RAB3GAP1 gene, but the neuronal mechanisms affected by its loss remain unclear. Recent work in the O’Sullivan lab at UCD have led to the creation of an in vivo model of WMS using CRISPR/Cas9 to knock out Rab3GAP1 in the ‘fruit fly Drosophila melanogaster. Rab3GAP1 knockout flies exhibit reduced lifespan and significant motor deficits, effectively modelling core features of WMS in a genetically tractable system and offering a valuable system for functional drug screening. This project aims to leverage this novel model to accelerate therapeutic discovery by screening for drugs that rescue neurological function. I will test three compounds: Idebenone, LXR-623, and N-acetylcysteine, selected for their roles in pathways linked to WMS. By evaluating their impact on motor performance and survival in Rab3GAP1 knockout flies, my work will help identify compounds that restore neurological function. The ultimate goal is to fast-track potential therapies for WMS and shed light on its poorly understood biology. This project could pave the way for urgently needed treatments in this currently untreatable condition.
