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000154831 1001_ $$0P:(DE-2719)2340744$$aColombo, Alessio Vittorio$$b0$$eFirst author$$udzne
000154831 245__ $$aLoss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
000154831 260__ $$a[London]$$bNature Publishing Group UK$$c2021
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000154831 520__ $$aNiemann-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.
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000154831 588__ $$aDataset connected to CrossRef, Journals: pub.dzne.de
000154831 650_2 $$2MeSH$$aAnimals
000154831 650_2 $$2MeSH$$aBlotting, Western
000154831 650_2 $$2MeSH$$aCells, Cultured
000154831 650_2 $$2MeSH$$aCholesterol: metabolism
000154831 650_2 $$2MeSH$$aFemale
000154831 650_2 $$2MeSH$$aHumans
000154831 650_2 $$2MeSH$$aIntracellular Signaling Peptides and Proteins: genetics
000154831 650_2 $$2MeSH$$aIntracellular Signaling Peptides and Proteins: metabolism
000154831 650_2 $$2MeSH$$aMale
000154831 650_2 $$2MeSH$$aMass Spectrometry
000154831 650_2 $$2MeSH$$aMice
000154831 650_2 $$2MeSH$$aMice, Inbred C57BL
000154831 650_2 $$2MeSH$$aMice, Knockout
000154831 650_2 $$2MeSH$$aMicroglia: metabolism
000154831 650_2 $$2MeSH$$aMyelin Sheath: metabolism
000154831 650_2 $$2MeSH$$aNiemann-Pick C1 Protein
000154831 650_2 $$2MeSH$$aNiemann-Pick Disease, Type C: genetics
000154831 650_2 $$2MeSH$$aNiemann-Pick Disease, Type C: metabolism
000154831 650_2 $$2MeSH$$aPhagocytosis: genetics
000154831 650_2 $$2MeSH$$aPhagocytosis: physiology
000154831 650_2 $$2MeSH$$aProteomics: methods
000154831 7001_ $$0P:(DE-2719)2813128$$aDinkel, Lina$$b1$$udzne
000154831 7001_ $$0P:(DE-2719)2810938$$aMüller, Stephan A$$b2$$udzne
000154831 7001_ $$0P:(DE-2719)2812269$$aSebastian Monasor, Laura$$b3$$udzne
000154831 7001_ $$0P:(DE-HGF)0$$aSchifferer, Martina$$b4
000154831 7001_ $$0P:(DE-2719)2812590$$aCantuti-Castelvetri, Ludovico$$b5$$udzne
000154831 7001_ $$0P:(DE-2719)2811955$$aKönig, Jasmin$$b6$$udzne
000154831 7001_ $$aVidatic, Lea$$b7
000154831 7001_ $$aBremova-Ertl, Tatiana$$b8
000154831 7001_ $$aLieberman, Andrew P.$$b9
000154831 7001_ $$aHecimovic, Silva$$b10
000154831 7001_ $$0P:(DE-2719)2811642$$aSimons, Mikael$$b11$$udzne
000154831 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F.$$b12$$udzne
000154831 7001_ $$aStrupp, Michael$$b13
000154831 7001_ $$aSchneider, Susanne A.$$b14
000154831 7001_ $$0P:(DE-2719)2442036$$aTahirovic, Sabina$$b15$$eLast author$$udzne
000154831 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-021-21428-5$$gVol. 12, no. 1, p. 1158$$n1$$p1158$$tNature Communications$$v12$$x2041-1723$$y2021
000154831 8564_ $$uhttps://www.nature.com/articles/s41467-021-21428-5
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