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

Colombo, Alessio; Dinkel, Lina; Mueller, Stephan A.; Monasor, Laura Sebastian; Schifferer, Martina; Cantuti-Castelvetri, Ludovico; Koenig, Jasmin; Vidatic, Lea; Bremova-Ertl, Tatiana; Lieberman, Andrew P.; Hecimovic, Silva; Simons, Mikael; Lichtenthaler, Stefan F.; Strupp, Michael; Schneider, Susanne A. und Tahirovic, Sabina (2021): Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. In: Nature Communications, Bd. 12, Nr. 1, 1158

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198