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

• Published in: Nature communications 2021-02, Vol.12 (1), p.1158-1158, Article 1158
• Main Authors: Colombo, Alessio, Dinkel, Lina, Müller, Stephan A., Sebastian Monasor, Laura, Schifferer, Martina, Cantuti-Castelvetri, Ludovico, König, Jasmin, Vidatic, Lea, Bremova-Ertl, Tatiana, Lieberman, Andrew P., Hecimovic, Silva, Simons, Mikael, Lichtenthaler, Stefan F., Strupp, Michael, Schneider, Susanne A., Tahirovic, Sabina
• Format: Article
• Language: English
• Subjects: 13; 14; 631/337; 631/378; 631/80; 64; 96; Animal models; Animals; Blood; Blotting, Western; Cell culture; Cells, Cultured; Children; Cholesterol - metabolism; Defects; Female; Humanities and Social Sciences; Humans; Immune system; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Lipids; Lysosomes; Macrophages; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; multidisciplinary; Mutation; Myelin; Myelin Sheath - metabolism; Neurodegenerative diseases; Niemann-Pick disease; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Disease, Type C - metabolism; Npc1 protein; Phagocytes; Phagocytosis - genetics; Phagocytosis - physiology; Phenotypes; Protein transport; Proteomics - methods; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21428-5

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.