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

Colombo, A; Dinkel, L.; Müller, S. A.; Sebastian Monasor, L.; Schifferer, M.; Cantuti-Castelvetri, L.; König, J.; Vidatic, Lea; Bremova-Ertl, T.; Lieberman, A.; Hećimović, Silva; Simons, M.; Lichtenthaler, S. F.; Strupp, M.; Schneider, S. A.; Tahirović, S. (2021) Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nature communications, 12 (1). ISSN 2041-1723

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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.

Item Type: Article
Uncontrolled Keywords: lipid trafficking ; microglia ; NPC ; phagocytic impairment ; proteome
Subjects: BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions: Division of Molecular Medicine
Project titleProject leaderProject codeProject type
Molekularni mehanizam neurodegeneracije u Niemann-Pickovoj bolesti tip CKatušić Hećimović, SilvaIP-2016-06-2799HRZZ
Depositing User: Dr. sc. Silva Katušić Hećimović
Date Deposited: 01 Feb 2022 13:30
DOI: 10.1038/s41467-021-21428-5

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