Niemann-Pick disease type C2 protein (NPC2) (NPC2)

Niemann-Pick disease type C2 protein (NPC2) is a small, soluble lysosomal glycoprotein that plays a critical role in the egress of unesterified cholesterol from the endosomal/lysosomal system [UniProt]. It acts as a cholesterol chaperone within the lysosomal lumen, binding cholesterol and transferring it to the membrane-bound NPC1 protein for transport into the cytosol [PubMed]. Mutations in the NPC2 gene lead to Niemann-Pick disease type C2, a rare and fatal autosomal recessive lysosomal storage disorder characterized by the accumulation of cholesterol and sphingolipids in various tissues, particularly the brain, liver, and lungs [NIH]. Clinically, this manifests as progressive neurodegeneration, ataxia, and vertical supranuclear gaze palsy [MedlinePlus]. Therapeutic strategies include the use of pharmacological chaperones like arimoclomol and substrate reduction therapies like miglustat, which aim to mitigate the biochemical and clinical progression of the disease [FDA, Wikipedia]. NPC2 also facilitates the presentation of lipid antigens to natural killer T (NKT) cells and has been identified as a factor in filovirus entry, where it competes with viral glycoproteins for binding to NPC1 [PubMed, Preprints.org].

Other names

Epididymal secretory protein E1HE1NP-C2NPC intracellular cholesterol transporter 2EDDM1

Therapeutic mechanisms include pharmacological chaperoning to stabilize the protein, substrate reduction to decrease lipid load, and cholesterol mobilization to bypass the transport defect [PubMed, FDA].