PUBLICATION
NPC1 links cholesterol trafficking to microglial morphology via the gastrosome
- Authors
- Zareba, J., Cattaneo, E.F., Villani, A., Othman, A., Streb, S., Peri, F.
- ID
- ZDB-PUB-241006-5
- Date
- 2024
- Source
- Nature communications 15: 86388638 (Journal)
- Registered Authors
- Peri, Francesca, Villani, Ambra
- Keywords
- none
- MeSH Terms
-
- Brain/metabolism
- Brain/pathology
- Microglia*/metabolism
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Niemann-Pick Disease, Type C*/genetics
- Niemann-Pick Disease, Type C*/metabolism
- Niemann-Pick Disease, Type C*/pathology
- Cholesterol*/metabolism
- Fibroblasts/metabolism
- Mice
- Humans
- Macrophages/metabolism
- Phagocytosis
- Niemann-Pick C1 Protein*
- Zebrafish*
- Animals
- Neurons/metabolism
- PubMed
- 39366931 Full text @ Nat. Commun.
Citation
Zareba, J., Cattaneo, E.F., Villani, A., Othman, A., Streb, S., Peri, F. (2024) NPC1 links cholesterol trafficking to microglial morphology via the gastrosome. Nature communications. 15:86388638.
Abstract
Microglia play important roles in brain development and homeostasis by removing dying neurons through efferocytosis. Morphological changes in microglia are hallmarks of many neurodegenerative conditions, such as Niemann-Pick disease type C. Here, NPC1 loss causes microglia to shift from a branched to an ameboid form, though the cellular basis and functional impact of this change remain unclear. Using zebrafish, we show that NPC1 deficiency causes an efferocytosis-dependent expansion of the microglial gastrosome, a collection point for engulfed material. In vivo and in vitro experiments on microglia and mammalian macrophages demonstrate that NPC1 localizes to the gastrosome, and its absence leads to cholesterol accumulation in this compartment. NPC1 loss and neuronal cell death synergistically affect gastrosome size and cell shape, increasing the sensitivity of NPC1-deficient cells to neuronal cell death. Finally, we demonstrate conservation of cholesterol accumulation and gastrosome expansion in NPC patient-derived fibroblasts, offering an interesting target for further disease investigation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping