Journal Article

DZNE-2021-00409

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Colombo, A. V. (First author)DZNE* ; Dinkel, L.DZNE* ; Müller, S. A.DZNE* ; Sebastian Monasor, L.DZNE* ; Schifferer, M. ; Cantuti-Castelvetri, L.DZNE* ; König, J.DZNE* ; Vidatic, L. ; Bremova-Ertl, T. ; Lieberman, A. P. ; Hecimovic, S. ; Simons, M.DZNE* ; Lichtenthaler, S. F.DZNE* ; Strupp, M. ; Schneider, S. A. ; Tahirovic, S. (Last author)DZNE*

2021
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-021-21428-5

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.

Keyword(s): Animals (MeSH) ; Blotting, Western (MeSH) ; Cells, Cultured (MeSH) ; Cholesterol: metabolism (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Intracellular Signaling Peptides and Proteins: genetics (MeSH) ; Intracellular Signaling Peptides and Proteins: metabolism (MeSH) ; Male (MeSH) ; Mass Spectrometry (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Microglia: metabolism (MeSH) ; Myelin Sheath: metabolism (MeSH) ; Niemann-Pick C1 Protein (MeSH) ; Niemann-Pick Disease, Type C: genetics (MeSH) ; Niemann-Pick Disease, Type C: metabolism (MeSH) ; Phagocytosis: genetics (MeSH) ; Phagocytosis: physiology (MeSH) ; Proteomics: methods (MeSH)

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Contributing Institute(s):

1. Ex vivo models (AG Tahirovic)
2. Neuroproteomics (AG Lichtenthaler)
3. Molecular Neurobiology (AG Simons)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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