Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Alessio Colombo, Lina Dinkel, Stephan A. Müller, Laura Sebastian Monasor, Martina Schifferer, Ludovico Cantuti-Castelvetri, Jasmin König, Lea Vidatic, Tatiana Bremova-Ertl, Andrew P. Lieberman, Silva Hecimovic, Mikael Simons, Stefan F. Lichtenthaler, Michael Strupp, Susanne A. Schneider and Sabina Tahirovic ()
Additional contact information
Alessio Colombo: German Center for Neurodegenerative Diseases (DZNE) Munich
Lina Dinkel: German Center for Neurodegenerative Diseases (DZNE) Munich
Stephan A. Müller: German Center for Neurodegenerative Diseases (DZNE) Munich
Laura Sebastian Monasor: German Center for Neurodegenerative Diseases (DZNE) Munich
Martina Schifferer: Munich Cluster for Systems Neurology (SyNergy)
Ludovico Cantuti-Castelvetri: German Center for Neurodegenerative Diseases (DZNE) Munich
Jasmin König: German Center for Neurodegenerative Diseases (DZNE) Munich
Lea Vidatic: Division of Molecular Medicine, Ruder Boskovic Institute
Tatiana Bremova-Ertl: Ludwig-Maximilians University
Andrew P. Lieberman: University of Michigan
Silva Hecimovic: Division of Molecular Medicine, Ruder Boskovic Institute
Mikael Simons: German Center for Neurodegenerative Diseases (DZNE) Munich
Stefan F. Lichtenthaler: German Center for Neurodegenerative Diseases (DZNE) Munich
Michael Strupp: Ludwig-Maximilians University
Susanne A. Schneider: Ludwig-Maximilians University
Sabina Tahirovic: German Center for Neurodegenerative Diseases (DZNE) Munich

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21428-5

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DOI: 10.1038/s41467-021-21428-5

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