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A Drosophila model of mucopolysaccharidosis IIIB

ABSTRACT: Mucopolysaccharidosis IIIB (MPS IIIB) is a rare genetic disorder caused by defects in α-N-acetylglucosaminidase, which breaks down extracellular heparan sulfate. Symptoms progress from hyperactivity and sleep disruptions during childhood to severe neurodegeneration during adolescence. To generate an MPS IIIB model in the fruitfly, Drosophila melanogaster, we introduced mutations in the corresponding fly enzyme that correlate with patient mutations. The fly model recapitulates sleep fragmentation and hyperactivity observed in patients and enlarged lysosomes in the brain. Genes associated with synaptic function and neurodevelopment showed altered expression in the brain. The Drosophila model can enable future development of therapies for MPS IIIB.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE269032 | GEO | 2025/03/26

REPOSITORIES: GEO

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Project description:Mucopolysaccharidosis (MPS) VII is a lysosomal storage disorder characterized by deficient activity of β-glucuronidase, leading to progressive accumulation of incompletely degraded heparan, dermatan and chondroitin sulfate glycosaminoglycans (GAGs). Patients with MPS VII exhibit progressive skeletal deformity including kyphoscoliosis and joint dysplasia, which decrease quality of life and increase mortality. Previously, using the naturally-occurring canine model, we demonstrated that one of the earliest skeletal abnormalities to manifest in MPS VII is failed initiation of secondary ossification in vertebrae and long bones at the requisite postnatal developmental stage. The objective of this study was to obtain global insights into the molecular mechanisms underlying this failed initiation of secondary ossification using whole transcriptome sequencing (RNA-Seq). Epiphyseal tissue was isolated from the vertebrae of control and MPS VII affected dogs at 9 and 14 days-of-age (n=5 for each group). Differences in global gene expression across this developmental window for both cohorts were established using RNA-Seq. A targeted analysis focused on signaling pathways important in the regulation of endochondral ossification, and a subset of gene expression changes were validated using qPCR. Principal Component Analysis revealed clustering of samples from each group, indicating clear effects of both age and disease state. At 9 days-of-age, 1375 genes were significantly differentially expression between MPS VII and control, and by 14 days-of-age, this increased to 4719 genes. Osteoactivin (GPNMB) was the top upregulated gene in MPS VII at both ages. Targeted analysis revealed temporal changes in gene expression from 9 to 14 days-of-age in control samples consistent with chondrocyte maturation, cartilage resorption, and osteogenesis. In MPS VII samples, however, elements of key osteogenic pathways such as Wnt/β-catenin and BMP signaling were dysregulated. In conclusion, this study represents the first step towards identifying druggable therapeutic targets and putative biomarkers for bone disease in MPS VII patients during postnatal growth.

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A Drosophila model of mucopolysaccharidosis IIIB

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