Abstract
Niemann-Pick Type C (NPC) disease is a lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids in the endolysosomal system. NPC disease results from a defect in either of two distinct cholesterol-binding proteins: a transmembrane protein, NPC1, and a small soluble protein, NPC2. NPC1 and NPC2 are thought to function closely in the export of lysosomal cholesterol with both proteins binding cholesterol in vitro but they may have unrelated lysosomal roles. To investigate this possibility, we compared biochemical consequences of the loss of either protein. Analyses of lysosome-enriched subcellular fractions from brain and liver revealed similar decreases in buoyant densities of lysosomes from NPC1 or NPC2 deficient mice compared to controls. The subcellular distribution of both proteins was similar and paralleled a lysosomal marker. In liver, absence of either NPC1 or NPC2 resulted in similar alterations in the carbohydrate processing of the lysosomal protease, tripeptidyl peptidase I. These results highlight biochemical alterations in the lysosomal system of the NPC-mutant mice that appear secondary to lipid storage. In addition, the similarity in biochemical phenotypes resulting from either NPC1 or NPC2 deficiency supports models in which the function of these two proteins within lysosomes are linked closely.
Highlights
Niemann Pick Type C (NPC) disease is a neurovisceral lysosomal storage disease that results from mutations in either of two distinct genes: NPC1 or NPC2 (,5% of cases)
To exclude possible strain effects, we introduced the Npc2 mutant allele into a BALB/c background by backcrossing and compared the phenotype of these congenic animals with the Npc1 mutant in the same strain (Fig.1)
We find that mice lacking NPC1 have the shortest life span with median survival 73 days (95% confidence interval (c.i.), 69 to 75 days)
Summary
Niemann Pick Type C (NPC) disease is a neurovisceral lysosomal storage disease that results from mutations in either of two distinct genes: NPC1 (accounting for ,95% of cases) or NPC2 (,5% of cases). Diseases arising from mutations in either gene are clinically indistinguishable and are characterized by an accumulation of cholesterol and other lipids within the lysosomes of affected individuals (reviewed in [1,2]). NPC1 encodes the endolysosomal membrane protein NPC1, a 1278 amino acid glycoprotein with 13 transmembrane segments and a sterolsensing domain [3] that binds sterols including cholesterol [4,5,6]. NPC2 encodes a 132 amino-acid soluble glycoprotein, NPC2, that primarily localizes to lysosomes [7,8] and which binds cholesterol and other sterols [9,10,11,12]. Recent biochemical studies indicate that NPC2 can facilitate the intermembrane transfer of cholesterol [14,15] and can transfer it to NPC1
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