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

## TL;DR

This study shows that lysosomal exocytosis and disrupted growth factor signaling contribute to cartilage problems in a zebrafish model of a genetic disorder.

## Contribution

The study reveals a new connection between lysosomal exocytosis and altered growth factor signaling in mucopolysaccharidosis type IVA.

## Key findings

- Loss of galns increases lysosomal exocytosis in developing cartilage of mutant zebrafish.
- Increased exocytosis is linked to reduced cathepsin activity and lower TGFβ and BMP signaling.
- Altered glycosaminoglycan levels are observed in intracellular and extracellular compartments.

## Abstract

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.

Summary: Loss of galns enhances lysosomal exocytosis in developing cartilage of mutant zebrafish. Increased exocytosis is associated with reduced cathepsin activity and lower levels of TGFβ and BMP signaling.