Npc1, Niemann-Pick type C1, is an integral membrane protein on the limiting membrane of late endosome/lysosome. It is crucial for post-lysosomal cholesterol trafficking, accepting cholesterol from NPC2 and mediating its transport to endoplasmic reticulum and plasma membrane, thus maintaining lipid homeostasis [3]. This process is essential for various cellular functions and is linked to multiple biological pathways, including mTORC1 signaling which couples cholesterol sensing to organelle homeostasis [1].

In Npc1-deficient models, such as Npc1 -/- mice, loss of Npc1 causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration, typical of Niemann-Pick type C disease [1]. In zebrafish, Npc1 deficiency causes microglia to change from a branched to an ameboid form and an efferocytosis-dependent expansion of the microglial gastrosome [2]. In NPC1-KO melanoma cells, there is decreased pigmentation due to defective processing and localization of tyrosinase [4].

In conclusion, Npc1 is essential for maintaining cholesterol and lipid homeostasis. Studies using Npc1-KO or related loss-of-function models have revealed its role in diseases like Niemann-Pick type C, neurodegeneration, and have also shown its impact on microglial morphology and melanosome maturation. These models significantly contribute to understanding the mechanisms underlying these disease conditions and related biological processes [1,2,4].

References:

1. Davis, Oliver B, Shin, Hijai R, Lim, Chun-Yan, Ordonez, M Paulina, Zoncu, Roberto. 2020. NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C. In Developmental cell, 56, 260-276.e7. doi:10.1016/j.devcel.2020.11.016. https://pubmed.ncbi.nlm.nih.gov/33308480/

2. Zareba, Joanna, Cattaneo, Elena F, Villani, Ambra, Streb, Sebastian, Peri, Francesca. 2024. NPC1 links cholesterol trafficking to microglial morphology via the gastrosome. In Nature communications, 15, 8638. doi:10.1038/s41467-024-52874-6. https://pubmed.ncbi.nlm.nih.gov/39366931/

3. Yu, Xiao-Hua, Jiang, Na, Yao, Ping-Bo, Cayabyab, Francisco S, Tang, Chao-Ke. 2013. NPC1, intracellular cholesterol trafficking and atherosclerosis. In Clinica chimica acta; international journal of clinical chemistry, 429, 69-75. doi:10.1016/j.cca.2013.11.026. https://pubmed.ncbi.nlm.nih.gov/24296264/

4. Rus, Alina Adriana, Militaru, Ioana V, Popa, Ioana, Platt, Frances M, Petrescu, Ștefana M. 2023. NPC1 plays a role in the trafficking of specific cargo to melanosomes. In The Journal of biological chemistry, 299, 105024. doi:10.1016/j.jbc.2023.105024. https://pubmed.ncbi.nlm.nih.gov/37423302/