Home > Publications Database > Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia > print

001     154831
005     20230915092318.0
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024 7 _ |a 10.1038/s41467-021-21428-5
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100 1 _ |a Colombo, Alessio Vittorio
|0 P:(DE-2719)2340744
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245 _ _ |a Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
260 _ _ |a [London]
|c 2021
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Blotting, Western
|2 MeSH
650 _ 2 |a Cells, Cultured
|2 MeSH
650 _ 2 |a Cholesterol: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Intracellular Signaling Peptides and Proteins: genetics
|2 MeSH
650 _ 2 |a Intracellular Signaling Peptides and Proteins: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Mass Spectrometry
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650 _ 2 |a Mice
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650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Mice, Knockout
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650 _ 2 |a Microglia: metabolism
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650 _ 2 |a Myelin Sheath: metabolism
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650 _ 2 |a Niemann-Pick C1 Protein
|2 MeSH
650 _ 2 |a Niemann-Pick Disease, Type C: genetics
|2 MeSH
650 _ 2 |a Niemann-Pick Disease, Type C: metabolism
|2 MeSH
650 _ 2 |a Phagocytosis: genetics
|2 MeSH
650 _ 2 |a Phagocytosis: physiology
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650 _ 2 |a Proteomics: methods
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700 1 _ |a Dinkel, Lina
|0 P:(DE-2719)2813128
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700 1 _ |a Müller, Stephan A
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700 1 _ |a Sebastian Monasor, Laura
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700 1 _ |a Schifferer, Martina
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700 1 _ |a Cantuti-Castelvetri, Ludovico
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700 1 _ |a König, Jasmin
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700 1 _ |a Vidatic, Lea
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700 1 _ |a Bremova-Ertl, Tatiana
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700 1 _ |a Lieberman, Andrew P.
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700 1 _ |a Hecimovic, Silva
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700 1 _ |a Simons, Mikael
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700 1 _ |a Lichtenthaler, Stefan F.
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700 1 _ |a Strupp, Michael
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700 1 _ |a Schneider, Susanne A.
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700 1 _ |a Tahirovic, Sabina
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773 _ _ |a 10.1038/s41467-021-21428-5
|g Vol. 12, no. 1, p. 1158
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|t Nature Communications
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|y 2021
|x 2041-1723
856 4 _ |u https://www.nature.com/articles/s41467-021-21428-5
856 4 _ |u https://pub.dzne.de/record/154831/files/7830.pdf
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