NPC1

Niemann-Pick disease, type C1 (NPC1) is a membrane is_associated_with::protein that mediates intracellular cholesterol trafficking in mammals. In humans it is encoded by the NPC1 is_associated_with::gene (chromosome location 18q11).

Function
NPC1 was identified as the gene that when mutated, results in is_associated_with::Niemann-Pick disease, type C. Niemann-Pick disease, type C is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either NPC1 or NPC2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Approximately 95% of NPC patients are found to have mutations in the NPC1 gene.

NPC1 encodes a putative is_associated_with::integral membrane protein containing is_associated_with::sequence motifs consistent with a role in intracellular transport of is_associated_with::cholesterol to post-lysosomal destinations.

Obesity
Mutations in the NPC1 gene have been strongly linked with is_associated_with::obesity. A genome-wide association study identified NPC1 mutations as a risk factor in childhood obesity and adult morbid obesity, and 1,416 age-matched normal weight controls. Mutations in NPC1 were also correlated with ordinary weight gain in the population. Previous studies in mice have suggested that the NPC1 gene has a role in controlling appetite, as mice with a non-functioning NPC1 gene suffer late-onset weight loss and have poor food intake. NPC1 gene variant could account for around 10 per cent of all childhood obesity and about 14 per cent of adult morbid obesity cases.

HIV-AIDS
Cholesterol pathways play an important role at multiple stages during the HIV-1 infection cycle. HIV-1 fusion, entry, assembly, and budding occur at cholesterol-enriched microdomains called is_associated_with::lipid rafts. The HIV-1 accessory protein, Nef, has been shown to induce many genes involved in cholesterol biosynthesis and homeostasis. Intracellular cholesterol trafficking pathways mediated by NPC1 are needed for efficient HIV-1 production.

Ebola virus
The human Niemann–Pick C1 (NPC1) cholesterol transporter appears to be essential for is_associated_with::Ebola virus infection: a series of independent studies have presented evidence that Ebola virus enters human cells after binding to NPC1. When cells from Niemann Pick Type C patients lacking this transporter were exposed to Ebola virus in the laboratory, the cells survived and appeared impervious to the virus, further indicating that Ebola relies on NPC1 to enter cells; mutations in the NPC1 gene in humans were conjectured as a possible mode to make some individuals resistant to this deadly viral disease. The same studies described similar results with Ebola's cousin in the is_associated_with::filovirus group, is_associated_with::Marburg virus, showing that it too needs NPC1 to enter cells. Furthermore, NPC1 was shown to be critical to is_associated_with::filovirus entry because it mediates infection by binding directly to the is_associated_with::viral envelope glycoprotein. A later study confirmed the findings that NPC1 is a critical is_associated_with::filovirus receptor that mediates infection by binding directly to the is_associated_with::viral envelope glycoprotein and that the second lysosomal domain of NPC1 mediates this binding.

In one of the original studies, a is_associated_with::small molecule was shown to inhibit Ebola virus infection by preventing the virus glycoprotein from binding to NPC1. In the other study, mice that were heterozygous for NPC1 were shown to be protected from lethal challenge with mouse adapted Ebola virus. Together, these studies suggest NPC1 may be potential therapeutic target for an Ebola anti-viral drug.

Mechanisms in Pathology
In a mouse model carrying the underlying mutation for is_associated_with::Niemann-Pick type C1 disease in the NPC1 protein, the expression of is_associated_with::Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased. MRF is a is_associated_with::transcription factor of critical importance in the development and maintenance of is_associated_with::myelin sheaths. A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits.