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Galns-deficiency enhances lysosomal exocytosis and alters cartilage development in zebrafish

ABSTRACT: Lysosomes represent a heterogenous population of organelles whose optimal function is essential for early tissue development. The importance of this is evidenced by the number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. While it is clear that macromolecular accumulation can adversely impact tissue development, the full breadth of downstream pathways driving pathology in these disorders is yet to be elucidated. Recent studies support the existence of mechanisms beyond lysosomal storage that profoundly influence early tissue formation. Among these, impaired mitochondrial function, oxidative stress, inflammation, and abnormal growth factor signaling have been linked to early pathology in multiple LSD. Studies in zebrafish models of mucolipidosis II and sialidosis identified a mechanism whereby inappropriate secretion of lysosomal cathepsins disrupts the TGF-ß related signaling pathways that control skeletal formation. Here we demonstrate that loss of galns (N-acetyl galactosamine-6-sulfatase) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Along with changes in the activity of several cathepsin proteases, enhanced exocytosis disrupts TGFß and BMP signaling altering cartilage and bone development in galnsm/m mutant larvae. Together these data suggest a role for altered growth factor signaling in MPSIVA skeletal pathology.

ORGANISM(S): Danio rerio

PROVIDER: GSE300957 | GEO | 2026/02/06

REPOSITORIES: GEO

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