%0 Journal Article
%A Colombo, Alessio Vittorio
%A Dinkel, Lina
%A Müller, Stephan A
%A Sebastian Monasor, Laura
%A Schifferer, Martina
%A Cantuti-Castelvetri, Ludovico
%A König, Jasmin
%A Vidatic, Lea
%A Bremova-Ertl, Tatiana
%A Lieberman, Andrew P.
%A Hecimovic, Silva
%A Simons, Mikael
%A Lichtenthaler, Stefan F.
%A Strupp, Michael
%A Schneider, Susanne A.
%A Tahirovic, Sabina
%T Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
%J Nature Communications
%V 12
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DZNE-2021-00409
%P 1158
%D 2021
%X 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.
%K Animals
%K Blotting, Western
%K Cells, Cultured
%K Cholesterol: metabolism
%K Female
%K Humans
%K Intracellular Signaling Peptides and Proteins: genetics
%K Intracellular Signaling Peptides and Proteins: metabolism
%K Male
%K Mass Spectrometry
%K Mice
%K Mice, Inbred C57BL
%K Mice, Knockout
%K Microglia: metabolism
%K Myelin Sheath: metabolism
%K Niemann-Pick C1 Protein
%K Niemann-Pick Disease, Type C: genetics
%K Niemann-Pick Disease, Type C: metabolism
%K Phagocytosis: genetics
%K Phagocytosis: physiology
%K Proteomics: methods
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33627648
%$ 33627648
%2 pmc:PMC7904859
%R 10.1038/s41467-021-21428-5
%U https://pub.dzne.de/record/154831