Enhanced lysosomal exocytosis and altered growth factor signaling are associated with cartilage pathology in a model of mucopolysaccharidosis type IVA

This is the authors' abstract. We don't add key points for this paper.

Optimal lysosomal function is essential for early tissue development. This is evidenced by the large number of inherited disorders, collectively called the lysosomal storage disorders (LSDs), caused by lysosomal dysfunction. Although it is clear that macromolecular accumulation adversely impacts tissue development, the breadth of downstream pathways contributing to pathology has yet to be elucidated. Multiple studies indicate that mechanisms beyond lysosomal storage also profoundly influence early tissue formation. Of these, abnormal growth factor signaling has been linked to pathology in several different LSDs. Recent work in a zebrafish model of sialidosis demonstrated that mislocalizing lysosomal cathepsins by increased exocytosis disrupts the TGFβ-related signaling pathways that control skeletal formation. Here, we show that loss of N-acetyl galactosamine-6-sulfatase (galns) also enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Unlike in sialidosis, however, in galns mutants, increased exocytosis was associated with reduced cathepsin activity, lower levels of TGFβ and BMP signaling, and altered abundance of intracellular and extracellular glycosaminoglycans. Together, these data highlight a role for lysosomal exocytosis and protease-mediated alterations in growth factor signaling in the onset of mucopolysaccharidosis type IVA skeletal pathology.