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
|
Text
Colombo__2021__Loss_of_NPC1.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (7MB) | Preview |
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: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurology |
UniBE Contributor: |
Brémovà-Ertl, Tatiana |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2041-1723 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Chantal Kottler |
Date Deposited: |
12 Jul 2021 16:01 |
Last Modified: |
05 Dec 2022 15:51 |
Publisher DOI: |
10.1038/s41467-021-21428-5 |
PubMed ID: |
33627648 |
BORIS DOI: |
10.48350/157355 |
URI: |
https://boris.unibe.ch/id/eprint/157355 |
Actions (login required)
 |
Edit item |