Npc2, also known as HE1, is a crucial gene encoding a 132-amino-acid glycoprotein. It functions as a lysosomal cholesterol transporter, working in coordination with Npc1 in the intralysosomal transport and efflux of cholesterol [1,2,4]. This process is essential for normal cholesterol trafficking within cells, and disruption of this function can lead to Niemann-Pick C disease (NPC), a rare autosomal recessive disorder characterized by severe neurodegeneration [1,5]. Genetic models, such as mouse and zebrafish models, have been instrumental in studying Npc2 function.

In the Npc2-deficient mouse model (Npc2Gt(LST105)BygNya), pre-symptomatic six-week-old mice showed splenomegaly and neuropathological changes, especially in the cerebellum with initial Purkinje cell loss and neuroinflammation. By 12 weeks, they had growth retardation, tremor, cerebellar ataxia, splenomegaly, foam cell accumulation in multiple organs, brain atrophy, and severe neuroinflammation, resembling human NP-C2 disease [3]. The npc2-deficient zebrafish also exhibited low mobility, high anxiety-related response, and pathological changes in the nervous system, kidney, liver, and pancreas correlated with inflammatory responses, suggesting it may be a model of NPC disease [6].

In conclusion, Npc2 is vital for cholesterol trafficking, and its malfunction is linked to NPC disease. The Npc2-deficient mouse and zebrafish models have provided valuable insights into the pathological mechanisms of NPC disease, helping to understand the complex disease manifestation and potentially facilitating the development of new treatment strategies for this disorder [3,6].