TY  - JOUR
AU  - Colombo, Alessio Vittorio
AU  - Dinkel, Lina
AU  - Müller, Stephan A
AU  - Sebastian Monasor, Laura
AU  - Schifferer, Martina
AU  - Cantuti-Castelvetri, Ludovico
AU  - König, Jasmin
AU  - Vidatic, Lea
AU  - Bremova-Ertl, Tatiana
AU  - Lieberman, Andrew P.
AU  - Hecimovic, Silva
AU  - Simons, Mikael
AU  - Lichtenthaler, Stefan F.
AU  - Strupp, Michael
AU  - Schneider, Susanne A.
AU  - Tahirovic, Sabina
TI  - Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2021-00409
SP  - 1158
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Blotting, Western
KW  - Cells, Cultured
KW  - Cholesterol: metabolism
KW  - Female
KW  - Humans
KW  - Intracellular Signaling Peptides and Proteins: genetics
KW  - Intracellular Signaling Peptides and Proteins: metabolism
KW  - Male
KW  - Mass Spectrometry
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Microglia: metabolism
KW  - Myelin Sheath: metabolism
KW  - Niemann-Pick C1 Protein
KW  - Niemann-Pick Disease, Type C: genetics
KW  - Niemann-Pick Disease, Type C: metabolism
KW  - Phagocytosis: genetics
KW  - Phagocytosis: physiology
KW  - Proteomics: methods
LB  - PUB:(DE-HGF)16
C6  - pmid:33627648
C6  - 33627648
C2  - pmc:PMC7904859
DO  - DOI:10.1038/s41467-021-21428-5
UR  - https://pub.dzne.de/record/154831
ER  -