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000273921 037__ $$aDZNE-2024-01395
000273921 041__ $$aEnglish
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000273921 1001_ $$0P:(DE-2719)2813128$$aDinkel, Lina$$b0$$eFirst author
000273921 245__ $$aMyeloid cell-specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease.
000273921 260__ $$aWashington, DC$$bAAAS$$c2024
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000273921 520__ $$aNiemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N-acetyl-l-leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.
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000273921 650_7 $$2NLM Chemicals$$aNiemann-Pick C1 Protein
000273921 650_7 $$2NLM Chemicals$$aIntracellular Signaling Peptides and Proteins
000273921 650_7 $$2NLM Chemicals$$aNpc1 protein, mouse
000273921 650_7 $$2NLM Chemicals$$aBzrp protein, mouse
000273921 650_7 $$2NLM Chemicals$$aReceptors, GABA
000273921 650_7 $$2NLM Chemicals$$aNPC1 protein, human
000273921 650_2 $$2MeSH$$aAnimals
000273921 650_2 $$2MeSH$$aNiemann-Pick Disease, Type C: pathology
000273921 650_2 $$2MeSH$$aNiemann-Pick Disease, Type C: metabolism
000273921 650_2 $$2MeSH$$aNiemann-Pick C1 Protein
000273921 650_2 $$2MeSH$$aIntracellular Signaling Peptides and Proteins: metabolism
000273921 650_2 $$2MeSH$$aHumans
000273921 650_2 $$2MeSH$$aMicroglia: metabolism
000273921 650_2 $$2MeSH$$aMicroglia: pathology
000273921 650_2 $$2MeSH$$aMice
000273921 650_2 $$2MeSH$$aMyeloid Cells: metabolism
000273921 650_2 $$2MeSH$$aMyeloid Cells: pathology
000273921 650_2 $$2MeSH$$aReceptors, GABA: metabolism
000273921 650_2 $$2MeSH$$aDisease Models, Animal
000273921 650_2 $$2MeSH$$aGliosis: pathology
000273921 650_2 $$2MeSH$$aGliosis: metabolism
000273921 7001_ $$0P:(DE-2719)9002483$$aHummel, Selina$$b1
000273921 7001_ $$0P:(DE-2719)9002392$$aZenatti, Valerio$$b2
000273921 7001_ $$0P:(DE-2719)9002458$$aMalara, Mariagiovanna$$b3
000273921 7001_ $$0P:(DE-2719)9002700$$aTillmann, Yannik$$b4
000273921 7001_ $$0P:(DE-2719)2340744$$aColombo, Alessio Vittorio$$b5
000273921 7001_ $$0P:(DE-2719)2812269$$aSebastian Monasor, Laura$$b6
000273921 7001_ $$00000-0001-8119-326X$$aSuh, Jung H$$b7
000273921 7001_ $$00000-0003-2081-782X$$aLogan, Todd$$b8
000273921 7001_ $$00000-0001-6823-2981$$aRoth, Stefan$$b9
000273921 7001_ $$0P:(DE-2719)9002242$$aPaeger, Lars$$b10
000273921 7001_ $$00009-0009-9728-8162$$aHoffelner, Patricia$$b11
000273921 7001_ $$00009-0005-9426-0325$$aBludau, Oliver$$b12
000273921 7001_ $$0P:(DE-2719)2812225$$aSchmidt, Andree$$b13
000273921 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b14
000273921 7001_ $$0P:(DE-2719)2812260$$aSchifferer, Martina$$b15
000273921 7001_ $$0P:(DE-2719)9000236$$aNuscher, Brigitte$$b16
000273921 7001_ $$0P:(DE-2719)2811277$$aNjavro, Jasenka Rudan$$b17
000273921 7001_ $$0P:(DE-2719)9001400$$aPrestel, Matthias$$b18
000273921 7001_ $$00009-0007-6158-319X$$aBartos, Laura M$$b19
000273921 7001_ $$0P:(DE-2719)9001653$$aWind-Mark, Karin$$b20
000273921 7001_ $$aSlemann, Luna$$b21
000273921 7001_ $$00009-0006-9074-3474$$aHoermann, Leonie$$b22
000273921 7001_ $$00009-0007-3543-5329$$aKunte, Sebastian T$$b23
000273921 7001_ $$0P:(DE-2719)9001652$$aGnoerich, Johannes$$b24
000273921 7001_ $$00009-0007-4379-4436$$aLindner, Simon$$b25
000273921 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b26
000273921 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b27
000273921 7001_ $$0P:(DE-2719)2010112$$aPaquet, Dominik$$b28
000273921 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b29
000273921 7001_ $$00009-0005-0734-4994$$aBartenstein, Peter$$b30
000273921 7001_ $$00000-0001-9736-2283$$aFranzmeier, Nicolai$$b31
000273921 7001_ $$00000-0002-9069-2594$$aLiesz, Arthur$$b32
000273921 7001_ $$00000-0003-0338-7530$$aGrosche, Antje$$b33
000273921 7001_ $$00000-0002-7397-045X$$aBremova-Ertl, Tatiana$$b34
000273921 7001_ $$00000-0002-6528-7570$$aCatarino, Claudia$$b35
000273921 7001_ $$aBeblo, Skadi$$b36
000273921 7001_ $$aBergner, Caroline$$b37
000273921 7001_ $$aSchneider, Susanne A$$b38
000273921 7001_ $$00000-0002-9544-2279$$aStrupp, Michael$$b39
000273921 7001_ $$00000-0003-1032-1265$$aDi Paolo, Gilbert$$b40
000273921 7001_ $$0P:(DE-2719)9001539$$aBrendel, Matthias$$b41
000273921 7001_ $$0P:(DE-2719)2442036$$aTahirovic, Sabina$$b42$$eLast author
000273921 773__ $$0PERI:(DE-600)2518839-2$$a10.1126/scitranslmed.adl4616$$gVol. 16, no. 776, p. eadl4616$$n776$$peadl4616$$tScience translational medicine$$v16$$x1946-6234$$y2024
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