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Papers In Press, published online ahead of print September 21, 2005
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Dept. of Biological and Environmental Sciences, University of Helsinki, Division of Biochemistry, Helsinki FI-00014
Corresponding Author: eeva-liisa.eskelinen{at}helsinki.fi
Niemann-Pick disease type C (NPC), caused by mutations in NPC1 or NPC2 gene, is characterised by accumulation of unesterified cholesterol and other lipids in endo/lysosomal compartments. NPC2 is a small soluble lysosomal protein that is targeted to this compartment via a mannose 6-phosphate–inhibitable pathway. To get insight into the roles of mannose 6-phosphate receptors in NPC2 targeting, we here examine the trafficking and function of NPC2 in fibroblast lines deficient in one or both of the two mannose 6-phosphate receptors, MPR46 and MPR300. We demonstrate that either MPR alone is sufficient to transport NPC2 to the endo/lysosomal compartment, although MPR300 seems to be more efficient than MPR46. In the absence of both MPRs, NPC2 is secreted into the culture medium and only a small amount of intracellular NPC2 can be detected mainly in the endoplasmic reticulum. This leads to massive accumulation of unesterified cholesterol to the endo/lysosomal compartment of the MPR46/300 deficient fibroblasts, a phenotype similar to the NPC patient fibroblasts. In addition, we observed an upregulation of NPC1 protein and messenger RNA in the MPR double deficient cells. Taken together our results suggest that the lysosomal targeting of NPC2 is strictly dependent on MPRs in fibroblasts.
Revised on August 29, 2005
Accepted on September 20, 2005
Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation
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