Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Abstract

AbstractNiemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations inNpc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1-/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking inNpc1-/-microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies ofNpc1-/-microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novelex vivoassays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murineNpc1-/-microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.