Colombo, A; Dinkel, L.; Müller, S. A.; Sebastian Monasor, L.; Schifferer, M.; Cantuti-Castelvetri, L.; König, J.; Vidatic, Lea; Bremova-Ertl, T.; Lieberman, A.; Hećimović, Silva; Simons, M.; Lichtenthaler, S. F.; Strupp, M.; Schneider, S. A.; Tahirović, S.
(2021)
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.
Nature communications, 12
(1).
ISSN 2041-1723
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.
Actions (login required)
 |
View Item |
6941
WOS:000626609600001
Altmetric
Altmetric
