Drosophila melanogaster model of RVCL-S demonstrates age dependent disease progression

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a disease that causes deterioration of small vessels, affecting various organs: eyes, brain, liver, and others. The RVCL-S carriers have lower life expectancy. There is no cure available to date. The disease has been linked to mutations in TREX1 gene disrupting its cytoplasmic localization. To facilitate the disease mechanism investigation, we employed model organism D. melanogaster, identified human TREX1 ortholog cg3165 , and confirmed its vital significance to flies. Then, we expressed human TREX1 and its mutant form TREX1 V235Gfs in flies and used optical coherence microscopy (OCM) to monitor the dynamics of flies’ vascular system. We detected the relapse of fly dorsal vessel, movement impairment, and reduced longevity in TREX1 V235Gfs-expressing transgenic animals. Vascular deterioration and shorter life span recapitulate the RVCL-S manifestations in humans. We have established a robust quantitative Drosophila RVCL-S phenotypic system that can potentially serve as a screening platform for drug discovery and drug targets identification.