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@ARTICLE{Colombo:154831,
      author       = {Colombo, Alessio Vittorio and Dinkel, Lina and Müller,
                      Stephan A and Sebastian Monasor, Laura and Schifferer,
                      Martina and Cantuti-Castelvetri, Ludovico and König, Jasmin
                      and Vidatic, Lea and Bremova-Ertl, Tatiana and Lieberman,
                      Andrew P. and Hecimovic, Silva and Simons, Mikael and
                      Lichtenthaler, Stefan F. and Strupp, Michael and Schneider,
                      Susanne A. and Tahirovic, Sabina},
      title        = {{L}oss of {NPC}1 enhances phagocytic uptake and impairs
                      lipid trafficking in microglia},
      journal      = {Nature Communications},
      volume       = {12},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2021-00409},
      pages        = {1158},
      year         = {2021},
      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.},
      keywords     = {Animals / Blotting, Western / Cells, Cultured /
                      Cholesterol: metabolism / Female / Humans / Intracellular
                      Signaling Peptides and Proteins: genetics / Intracellular
                      Signaling Peptides and Proteins: metabolism / Male / Mass
                      Spectrometry / Mice / Mice, Inbred C57BL / Mice, Knockout /
                      Microglia: metabolism / Myelin Sheath: metabolism /
                      Niemann-Pick C1 Protein / Niemann-Pick Disease, Type C:
                      genetics / Niemann-Pick Disease, Type C: metabolism /
                      Phagocytosis: genetics / Phagocytosis: physiology /
                      Proteomics: methods},
      cin          = {AG Tahirovic / AG Lichtenthaler / AG Simons},
      ddc          = {500},
      cid          = {I:(DE-2719)1140003 / I:(DE-2719)1110006 /
                      I:(DE-2719)1110008},
      pnm          = {351 - Brain Function (POF4-351) / 352 - Disease Mechanisms
                      (POF4-352) / 351 - Brain Function (POF4-351) / 352 - Disease
                      Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352 /
                      G:(DE-HGF)POF4-351 / G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33627648},
      pubmed       = {33627648},
      pmc          = {pmc:PMC7904859},
      doi          = {10.1038/s41467-021-21428-5},
      url          = {https://pub.dzne.de/record/154831},
}