Npc1, or Niemann-Pick C1, is an integral membrane protein on the limiting membrane of late endosome/lysosome (LE/LY). It plays a crucial role in intracellular cholesterol trafficking, accepting cholesterol from NPC2 and mediating its transport from LE/LY to endoplasmic reticulum (ER) and plasma membrane. This process is essential for maintaining lipid homeostasis, and Npc1 is also involved in multiple biological pathways such as those related to organelle homeostasis and viral infections [3,4]. Genetic models, like knockout (KO) mouse models, have been instrumental in studying Npc1's functions.

In Npc1-deficient models, loss of this gene causes cholesterol accumulation within lysosomes. In Niemann-Pick type C (NPC) disease models, this leads to mTORC1 hyperactivation, disrupted mitochondrial function, and neurodegeneration. Genetic and pharmacologic mTORC1 inhibition can restore lysosomal proteolysis without correcting cholesterol storage, indicating that aberrant mTORC1 is a pathogenic driver downstream of cholesterol accumulation [1]. In microglia, Npc1 deficiency in zebrafish causes a shift from a branched to an ameboid form and an efferocytosis-dependent expansion of the gastrosome [2]. In addition, Npc1 knockout affects STING signalling in mice, with knockout of Npc1 priming and boosting STING signalling, which is required for severe neurological disease in Npc1-/-mice [5].

In conclusion, Npc1 is essential for regulating intracellular cholesterol trafficking and maintaining lipid homeostasis. Studies using Npc1 KO/CKO mouse models have revealed its critical role in diseases such as Niemann-Pick type C, where it is associated with neurodegeneration, mitochondrial dysfunction, and abnormal mTORC1 signalling. These models have also provided insights into its functions in microglial morphology and immune-related signalling pathways, highlighting its significance in understanding disease mechanisms.