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@ARTICLE{Dinkel:273921,
      author       = {Dinkel, Lina and Hummel, Selina and Zenatti, Valerio and
                      Malara, Mariagiovanna and Tillmann, Yannik and Colombo,
                      Alessio Vittorio and Sebastian Monasor, Laura and Suh, Jung
                      H and Logan, Todd and Roth, Stefan and Paeger, Lars and
                      Hoffelner, Patricia and Bludau, Oliver and Schmidt, Andree
                      and Müller, Stephan A and Schifferer, Martina and Nuscher,
                      Brigitte and Njavro, Jasenka Rudan and Prestel, Matthias and
                      Bartos, Laura M and Wind-Mark, Karin and Slemann, Luna and
                      Hoermann, Leonie and Kunte, Sebastian T and Gnoerich,
                      Johannes and Lindner, Simon and Simons, Mikael and Herms,
                      Jochen and Paquet, Dominik and Lichtenthaler, Stefan F and
                      Bartenstein, Peter and Franzmeier, Nicolai and Liesz, Arthur
                      and Grosche, Antje and Bremova-Ertl, Tatiana and Catarino,
                      Claudia and Beblo, Skadi and Bergner, Caroline and
                      Schneider, Susanne A and Strupp, Michael and Di Paolo,
                      Gilbert and Brendel, Matthias and Tahirovic, Sabina},
      title        = {{M}yeloid cell-specific loss of {NPC}1 in mice
                      recapitulates microgliosis and neurodegeneration in patients
                      with {N}iemann-{P}ick type {C} disease.},
      journal      = {Science translational medicine},
      volume       = {16},
      number       = {776},
      issn         = {1946-6234},
      address      = {Washington, DC},
      publisher    = {AAAS},
      reportid     = {DZNE-2024-01395},
      pages        = {eadl4616},
      year         = {2024},
      abstract     = {Niemann-Pick type C (NPC) disease is an inherited lysosomal
                      storage disorder mainly driven by mutations in the NPC1
                      gene, causing lipid accumulation within late
                      endosomes/lysosomes and resulting in progressive
                      neurodegeneration. Although microglial activation precedes
                      neuronal loss, it remains elusive whether loss of the
                      membrane protein NPC1 in microglia actively contributes to
                      NPC pathology. In a mouse model with depletion of NPC1 in
                      myeloid cells, we report severe alterations in microglial
                      lipidomic profiles, including the enrichment of
                      bis(monoacylglycero)phosphate, increased cholesterol, and a
                      decrease in cholesteryl esters. Lipid dyshomeostasis was
                      associated with microglial hyperactivity, marked by an
                      increase in translocator protein 18 kDa (TSPO). These
                      hyperactive microglia initiated a pathological cascade
                      resembling NPC-like phenotypes, including a shortened life
                      span, motor impairments, astrogliosis, neuroaxonal
                      pathology, and increased neurofilament light chain (NF-L), a
                      neuronal injury biomarker. As observed in the mouse model,
                      patients with NPC showed increased NF-L in the blood and
                      microglial hyperactivity, as visualized by TSPO-PET imaging.
                      Reduced TSPO expression in blood-derived macrophages of
                      patients with NPC was measured after N-acetyl-l-leucine
                      treatment, which has been recently shown to have beneficial
                      effects in patients with NPC, suggesting that TSPO is a
                      potential marker to monitor therapeutic interventions for
                      NPC. Conclusively, these results demonstrate that myeloid
                      dysfunction, driven by the loss of NPC1, contributes to NPC
                      disease and should be further investigated for therapeutic
                      targeting and disease monitoring.},
      keywords     = {Animals / Niemann-Pick Disease, Type C: pathology /
                      Niemann-Pick Disease, Type C: metabolism / Niemann-Pick C1
                      Protein / Intracellular Signaling Peptides and Proteins:
                      metabolism / Humans / Microglia: metabolism / Microglia:
                      pathology / Mice / Myeloid Cells: metabolism / Myeloid
                      Cells: pathology / Receptors, GABA: metabolism / Disease
                      Models, Animal / Gliosis: pathology / Gliosis: metabolism /
                      Niemann-Pick C1 Protein (NLM Chemicals) / Intracellular
                      Signaling Peptides and Proteins (NLM Chemicals) / Npc1
                      protein, mouse (NLM Chemicals) / Bzrp protein, mouse (NLM
                      Chemicals) / Receptors, GABA (NLM Chemicals) / NPC1 protein,
                      human (NLM Chemicals)},
      cin          = {AG Tahirovic / AG Herms / AG Lichtenthaler / AG Misgeld /
                      AG Haass / AG Simons},
      ddc          = {500},
      cid          = {I:(DE-2719)1140003 / I:(DE-2719)1110001 /
                      I:(DE-2719)1110006 / I:(DE-2719)1110000-4 /
                      I:(DE-2719)1110007 / I:(DE-2719)1110008},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39630885},
      doi          = {10.1126/scitranslmed.adl4616},
      url          = {https://pub.dzne.de/record/273921},
}