Lysosomal storage disorders (LSDs) result from defects in lysosomal catabolism and frequently present as pediatric neurodegenerative conditions. Mounting evidence suggests that inappropriate activation of innate immune cells actively contributes to the pathology in LSDs, strikingly similar to the reactive microgliosis observed in adult neurodegenerative conditions, such as Alzheimer’s disease. Despite observations indicating that aberrant activation of the immune system is an early event in many LSDs, and treatments such as bone marrow transplants or immunosuppression can be effective for some LSDs, the specific ways in which microglia and macrophages influence the onset or progression of these devastating pediatric diseases have not been thoroughly investigated.

To illuminate the role of the innate immune system in LSDs, we will generate “humanized” zebrafish models carrying LSD-specific coding mutations, perform detailed spatiotemporal analysis of the onset of neuroinflammation relative to neurodegeneration, and identify small molecule therapeutics for LSDs using drug screens.