Substrate reduction using a glucosamine analogue in Drosophila melanogaster and mouse models of Sanfilippo syndrome

Molecular Genetics and Metabolism, Год журнала: 2025, Номер 145(2), С. 109112 - 109112

Опубликована: Апрель 19, 2025

Mucopolysaccharidosis (MPS) types III A and C are inherited neurodegenerative disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism, leading to accumulation partially-degraded HS fragments. At present, there no approved treatments death is commonly second decade life. Several therapies have undergone pre-clinical evaluation for these conditions, including substrate reduction therapy, with most studied compound this class being isoflavone genistein. However, findings Phase clinical trial demonstrated that high dose oral genistein did not significantly improve neurodevelopmental outcomes patients MPS (Sanfilippo syndrome). Here, we tested an N-acetylglucosamine analogue, 4-deoxy-N-acetylglucosamine peracetate, as novel therapy HS-storing lysosomal storage such III. Treatment reduced levels cultured IIIA patient mouse fibroblasts time- dose-dependent manner. IIIC Drosophila fed peracetate contained less relative those raised on control diets. Likewise, improvements load within brain suggests crossed blood-brain barrier after administration. Although long-term studies needed, indicate 4-deoxy-GlcNAc may be beneficial slowing represent therapeutic potentially other disorders.

Язык: Английский

A Drosophila Model of Mucopolysaccharidosis IIIB

Genetics, Год журнала: 2024, Номер unknown

Опубликована: Дек. 31, 2024

Mucopolysaccharidosis type IIIB (MPS IIIB) is a rare lysosomal storage disorder caused by defects in alpha-N-acetylglucosaminidase (NAGLU) and characterized severe effects the central nervous system. Mutations NAGLU cause accumulation of partially degraded heparan sulfate lysosomes. The consequences these mutations on whole genome gene expression their causal relationships to neural degeneration remain unknown. Here, we used functional Drosophila melanogaster ortholog NAGLU, Naglu, develop fly model for MPS induced deletion (NagluKO), missense (NagluY160C), nonsense (NagluW422X) mutations. We activity monitoring system analyze sleep found sex- age-dependent hyperactivity mutant flies. Fluorescence microscopy brains using Lysotracker dye revealed significant increase acidic compartments. Differentially expressed genes determined from RNA sequencing are involved biological processes that affect development. A genetic interaction network constructed known interacting partners consists two major subnetworks, one which enriched associated with synaptic function other neurodevelopmental processes. Our data indicate dysfunction arising disruption breakdown has widespread steady state intracellular vesicle transport, including vesicles transmission. Evolutionary conservation fundamental predicts can serve as an vivo future development therapies related disorders.

Язык: Английский