NPC1 links cholesterol trafficking to microglial morphology via the gastrosome

• Published in: Nature communications Vol. 15; no. 1; pp. 8638 - 15
• Main Authors: Zareba, Joanna, Cattaneo, Elena F., Villani, Ambra, Othman, Alaa, Streb, Sebastian, Peri, Francesca
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/19; 14/28; 38; 631/250/1933; 631/378/1934; 631/80/642; 64; 64/116; Accumulation; Animals; Brain - metabolism; Brain - pathology; Cell death; Cell size; Cholesterol; Cholesterol - metabolism; Fibroblasts - metabolism; Homeostasis; Humanities and Social Sciences; Humans; In vivo methods and tests; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Macrophages; Macrophages - metabolism; Mice; Microglia; Microglia - metabolism; Morphology; Mortality; multidisciplinary; Neurons - metabolism; Niemann-Pick C1 Protein; Niemann-Pick disease; Niemann-Pick Disease, Type C - genetics; Niemann-Pick Disease, Type C - metabolism; Niemann-Pick Disease, Type C - pathology; Npc1 protein; Phagocytosis; Science; Science (multidisciplinary); Zebrafish; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52874-6

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. In Niemann-Pick type C, microglia display an ameboid shape. Here, the authors show that this is tied to neuronal engulfment and the expansion of the gastrosome, where cholesterol accumulates, making microglia more sensitive to neuronal cell death levels.