期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-21428-5
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资金
- NCL Foundation
- Alzheimer Forschung Initiative e.V. [18014]
- Alzheimer's Association Grant through the AD Strategic Fund [ADSF-21-831226-C]
- BMBF through JPND PMG-AD
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [EXC 2145 SyNergy, 390857198]
- N.I.H. [R01 NS063967]
- Croatian Science Foundation [IP-2016-06-2799]
- LMU Excellence Program for Clinician Scientists
- Verum-Stiftung
- Ara Parseghian Medical Research Foundation
Niemann-Pick type C disease is primarily caused by mutations in NPC1, leading to abnormal lipid storage in late endosomes/lysosomes. Research shows that NPC1 disruption significantly impairs microglial function, potentially triggering abnormalities in phagocytosis and myelin turnover in microglia before neuronal death.
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.
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