TY  - JOUR
AU  - Dinkel, Lina
AU  - Hummel, Selina
AU  - Zenatti, Valerio
AU  - Malara, Mariagiovanna
AU  - Tillmann, Yannik
AU  - Colombo, Alessio Vittorio
AU  - Sebastian Monasor, Laura
AU  - Suh, Jung H
AU  - Logan, Todd
AU  - Roth, Stefan
AU  - Paeger, Lars
AU  - Hoffelner, Patricia
AU  - Bludau, Oliver
AU  - Schmidt, Andree
AU  - Müller, Stephan A
AU  - Schifferer, Martina
AU  - Nuscher, Brigitte
AU  - Njavro, Jasenka Rudan
AU  - Prestel, Matthias
AU  - Bartos, Laura M
AU  - Wind-Mark, Karin
AU  - Slemann, Luna
AU  - Hoermann, Leonie
AU  - Kunte, Sebastian T
AU  - Gnoerich, Johannes
AU  - Lindner, Simon
AU  - Simons, Mikael
AU  - Herms, Jochen
AU  - Paquet, Dominik
AU  - Lichtenthaler, Stefan F
AU  - Bartenstein, Peter
AU  - Franzmeier, Nicolai
AU  - Liesz, Arthur
AU  - Grosche, Antje
AU  - Bremova-Ertl, Tatiana
AU  - Catarino, Claudia
AU  - Beblo, Skadi
AU  - Bergner, Caroline
AU  - Schneider, Susanne A
AU  - Strupp, Michael
AU  - Di Paolo, Gilbert
AU  - Brendel, Matthias
AU  - Tahirovic, Sabina
TI  - Myeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease.
JO  - Science translational medicine
VL  - 16
IS  - 776
SN  - 1946-6234
CY  - Washington, DC
PB  - AAAS
M1  - DZNE-2024-01395
SP  - eadl4616
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Niemann-Pick Disease, Type C: pathology
KW  - Niemann-Pick Disease, Type C: metabolism
KW  - Niemann-Pick C1 Protein
KW  - Intracellular Signaling Peptides and Proteins: metabolism
KW  - Humans
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Mice
KW  - Myeloid Cells: metabolism
KW  - Myeloid Cells: pathology
KW  - Receptors, GABA: metabolism
KW  - Disease Models, Animal
KW  - Gliosis: pathology
KW  - Gliosis: metabolism
KW  - Niemann-Pick C1 Protein (NLM Chemicals)
KW  - Intracellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - Npc1 protein, mouse (NLM Chemicals)
KW  - Bzrp protein, mouse (NLM Chemicals)
KW  - Receptors, GABA (NLM Chemicals)
KW  - NPC1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39630885
DO  - DOI:10.1126/scitranslmed.adl4616
UR  - https://pub.dzne.de/record/273921
ER  -