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

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1(-/-) microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential. Niemann-Pick type C disease is a rare childhood neurodegenerative disorder predominantly caused by mutations in NPC1, resulting in abnormal late endosomal and lysosomal defects. Here the authors show that NPC1 disruption largely impairs microglial function.

Automated summary

Niemann-Pick type C disease is primarily caused by mutations in NPC1, leading to abnormal lipid storage in late endosomes/lysosomes. Research shows that NPC1 disruption significantly impairs microglial function, potentially triggering abnormalities in phagocytosis and myelin turnover in microglia before neuronal death.