Exploring Cathepsin K as the Mechanistic Link Between Disrupted Lysosomal Acidification and Microglial Dysfunction

As proper lysosomal acidification, driven by Vacuolar-ATPases, is essential for microglial function, understanding how microglial function can be impaired by a loss of lysosomal acidification is broadly important and therapeutically relevant. I found that mutants with a loss of lysosomal acidification (atp6ap2 -/-) have less mature active cathepsin K and more preprocathepsin K when compared to siblings with normal lysosomal acidification (atp6ap2 +/+; +/-). Additionally, zebrafish larvae with normal lysosomal acidification show aggregation of cathepsin K within microglia, while atp6ap2 mutants have no detectable cathepsin K protein.