Niemann Pick C disease: lessons from zebrafish development

Niemann Pick C disease is a rare, fatal lipid-storage disorder with no known cure. 95% of patients carry mutations in NPC1 (Niemann-Pick disease, type C1), which encodes a protein involved in the intra-cellular trafficking of low-density lipoprotein (LDL)-derived cholesterol and plasma-derived glycolipids. Studies of mammalian models have shed light on pathological mechanisms caused by the mutation; now, Schwend et al. approach the issue from a developmental angle by identifying and studying the role of npc1 in the zebrafish embryo. They find that npc1 morphants display numerous abnormalities, including cholesterol mislocalisation, cell-movement defects and, at later stages of embryogenesis, cell death. Complementation of npc1 morphants with mouse Npc1 rescues the defect, indicating a high degree of gene homology between fish and mammals. Treatment of npc1 morphants with steroids also rescues the defects, suggesting that reduced steroidogenesis is responsible for pathology caused by npc1 loss of function. This study provides new clues for how to treat Niemann Pick C disease in humans, and suggests that the zebrafish embryo is a valid model to screen for novel therapies.