Niemann-Pick C Research Articles

Recent advances in elucidating Niemann-Pick C disease.

Lysosomal sequestration of endocytosed LDL-derived cholesterol, premature and abnormal enrichment of cholesterol in trans Golgi cisternae and accompanying anomalies in intracellular sterol trafficking are the hallmark phenotypic features of the Niemann-Pick C (NPC) lesion. A variable severity of these alterations has been observed, with only partial correlation between clinical and biochemical phenotypes. NPC also affects the metabolism of sphingolipids, and other biochemical abnormalities have been reported. Occurrence of neurofibrillary tangles in the brain of patients with a slowly progressive course is a recent intriguing observation. Genetic heterogeneity was established by cell hybridization and linkage studies. The two complementation groups could not be distinguished from each other by clinical, cellular or biochemical criteria, suggesting that the two gene products may interact or function sequentially. The major (> 90% of patients) NPC1 gene was mapped to 18q11 and recently isolated by positional cloning. The cDNA sequence predicts a 1278-amino acid protein, with 13 to 16 possible transmembrane regions and a putative cholesterol-sensing domain. Two murine models of the disease involving the same gene are known. The murine cDNA and the npc(nih) mutation have been characterized. Described homologies of the NPC1 protein are in line with its putative involvement in cellular cholesterol traffic.

Cholesterol reutilization during myelination of regenerating PNS axons is impaired in Niemann-Pick disease type C mice.

Niemann-Pick C (NPC) disease is an autosomal recessive lipidosis characterized by lysosomal accumulations of unesterified cholesterol. Cultured NPC cells exhibit a defect in the intracellular trafficking of LDL-derived cholesterol that leads to lysosomal accumulations of unesterified cholesterol. We found in a preliminary study that the myelination of regenerating axons was retarded in the NPC mouse following sciatic nerve crush. Because lipoprotein-mediated cholesterol transport is involved in myelination during nerve regeneration, we investigated whether this cholesterol reutilization pathway was perturbed in the NPC mouse. Mice received intraneural injections of [3H]acetate to label myelin cholesterol, and 2 weeks later the injected nerves were crushed above the injection site. Four weeks after crush, the nerves were examined by electron microscopic autoradiography. In normal mice, regeneration was well advanced, with thick myelin sheaths surrounding the regenerated axons and very little myelin debris remaining. The new myelin sheaths were well labeled, indicative of efficient cholesterol reutilization. In NPC mice, the new myelin sheaths were thinner and contained little label, indicative of retarded regeneration and little or no cholesterol reutilization. These data suggest the possibility of a causal link between compromised cholesterol reutilization and delayed or slowed regeneration of myelin sheaths.

Type C Niemann-Pick disease: dimethyl sulfoxide moderates abnormal LDL-cholesterol processing in mutant fibroblasts

Biochemical and cytochemical studies have revealed that abnormal processing of low-density-lipoprotein (LDL) cholesterol can be reversed in mutant Niemann-Pick C (NP-C) fibroblasts when 2% dimethyl sulfoxide (DMSO) is added to the culture medium. Both the excessive lysosomal accumulation of LDL cholesterol and the delayed induction of cellular homeostatic responses associated with the uptake of LDL by the mutant cells were substantially reversed by DMSO. DMSO appears to accelerate the intracellular mobilization of LDL-derived cholesterol through effects that may reflect enhanced membrane permeability or cholesterol solubilization.