A Drosophila Model of Mucopolysacchridosis IIIA

Mucopolysaccharidosis IIIA (MPS IIIA) is a rare lysosomal storage disorder that arises from inability to break down heparan sulfate (HS) because of mutations in the N-sulfoglucosamine sulfohydrolase (SGSH) gene. We used a deletion mutant of the Drosophila melanogaster Sgsh gene along with three point mutations analogous to mutations observed in patients (S64W, L89P, S301P) to show an increase in the average percent of area with lysosomal puncta in the fly brains of our mutants using Lysotracker. RNA sequencing of brains of mutant and control flies showed 441 (Knockout), 337 (S64W), 155 (L89P), and 96 (S301P) differentially expressed genes, including N-acetyl-alpha-glycosaminidase (Naglu) and N-acetylglucosamine 6-Sulfatase (GNS), which are both downstream from Sgsh in the HS catabolic pathway. Disruption of Sgsh expression impacts multiple interrelated biological processes, including developmental pathways, transcriptional regulation, RNA processing and nuclear transport, ribosome biogenesis, protein folding and proteolysis, metabolic pathways, and neurodevelopment. These observations indicate that D. melanogaster can serve as a model for MPS IIIA and lay the foundation for future comparative genomics approaches to assess the impact of background modifiers on variation in disease severity and penetrance.