SECONDARY IMPAIRMENT OF INTRACELLULAR CHOLESTEROL TRANSPORT IN CELLS WITH NIEMANN-PICK DISEASE TYPE C

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Niemann-Pick disease type C (NPC) is an autosomal recessive lipidosis resulting from mutations of the NPC1 or NPC2 gene, clinically characterized by hepatosplenomegaly and progressive neurological symptoms including vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Neurodegeneration in NPC shows a number of pathological features similar to those observed in Alzheimer disease. Biochemically, this disease is featured by a defect in intracellular trafficking of exogenous cholesterol that leads to the lysosomal and late-endosomal accumulation of unesterified cholesterol. Some reports have shown disturbance of cholesterol efflux in cells with NPC1, or NPC2 gene mutations, resulting in plasma lipid abnormalities including low levels of high-density lipoprotein (HDL) cholesterol as part of the phenotype in NPC. To elucidate the molecular basis for low HDL cholesterol in human plasma, mRNA expressions of 4 ATP-binding cassette (ABC) transporters related to lipid metabolism, ABCA1, ABCA3, ABCA7, and ABCG1, were analyzed in fibroblasts with NPC1 gene mutations by real-time RT-PCR using hybridization probes. These analyses were performed using two fibroblasts of NPC from a patient with two novel compound heterozygous NPC1 mutations, c.1891A>G and c.581_592delinsG, and a patient with other two novel compound heterozygous NPC1 mutations, c.2800C>T and c.3418G>A. Based on these analyses, the mRNA levels of ABCA1 and ABCG1 were significantly decreased in the fibroblasts. These findings suggest that secondary dysfunctions of ABCA1 and ABCG1 may cause impairment of cholesterol efflux in the peripheral cells, leading to low plasma levels of HDL cholesterol in NPC. Second, to clarify whether the secondary acid sphingomyelinase deficiency in NPC cells is related to the intracellular pathology of NPC, we investigated the effects of an acid sphingomyelinase inducer, butyrate, on the accumulation of unesterified cholesterol in NPC cells. The results demonstrated that correction of the secondary acid sphingomyelinase deficiency could ameliorate the extent of cholesterol accumulation.

SECONDARY IMPAIRMENT OF INTRACELLULAR CHOLESTEROL TRANSPORT IN CELLS WITH NIEMANN-PICK DISEASE TYPE C

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