Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
| Autor: | Martina Schifferer, Ludovico Cantuti-Castelvetri, Susanne A. Schneider, Sabina Tahirovic, Andrew P. Lieberman, Jasmin König, Lina Dinkel, Silva Hećimović, Laura Sebastian Monasor, Tatiana Bremova-Ertl, Lea Vidatic, Alessio Colombo, Stephan A. Müller, Stefan F. Lichtenthaler, Michael Strupp, Mikael Simons |
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| Jazyk: | chorvatština |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Proteomics Male Molecular biology metabolism [Myelin Sheath] General Physics and Astronomy metabolism [Microglia] Microgliosis Mass Spectrometry Myelin Mice 0302 clinical medicine hemic and lymphatic diseases Myelin Sheath Cells Cultured Mice Knockout Multidisciplinary Microglia Chemistry Intracellular Signaling Peptides and Proteins Niemann-Pick Disease Type C Phenotype 3. Good health Cell biology ddc medicine.anatomical_structure Cholesterol Female lipids (amino acids peptides and proteins) ddc:500 physiology [Phagocytosis] Niemann–Pick disease metabolism [Intracellular Signaling Peptides and Proteins] congenital hereditary and neonatal diseases and abnormalities Endosome Science Blotting Western 610 Medicine & health General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences metabolism [Niemann-Pick Disease Type C] Immune system Phagocytosis Niemann-Pick C1 Protein genetics [Niemann-Pick Disease Type C] medicine Animals Humans genetics [Phagocytosis] nutritional and metabolic diseases Basic Medical Sciences General Chemistry medicine.disease metabolism [Cholesterol] nervous system diseases lipid trafficking microglia NPC phagocytic impairment proteome Mice Inbred C57BL 030104 developmental biology Neuroscience genetics [Intracellular Signaling Peptides and Proteins] NPC1 methods [Proteomics] 030217 neurology & neurosurgery |
| Zdroj: | Nature communications Nature Communications 12(1), 1158 (2021). doi:10.1038/s41467-021-21428-5 Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-20 (2021) Colombo, Alessio; Dinkel, Lina; Müller, Stephan A; Sebastian Monasor, Laura; Schifferer, Martina; Cantuti-Castelvetri, Ludovico; König, Jasmin; Vidatic, Lea; Bremova-Ertl, Tatiana; Lieberman, Andrew P; Hecimovic, Silva; Simons, Mikael; Lichtenthaler, Stefan F; Strupp, Michael; Schneider, Susanne A; Tahirovic, Sabina (2021). Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nature Communications, 12(1), p. 1158. Springer Nature 10.1038/s41467-021-21428-5 |
| DOI: | 10.1038/s41467-021-21428-5 |
| Popis: | 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. Niemann-Pick type C disease is a rare childhood neurodegenerative disorder predominantly caused by mutations in NPC1, resulting in abnormal late endosomal and lysosomal defects. Here the authors show that NPC1 disruption largely impairs microglial function. |
| Databáze: | OpenAIRE |
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