Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewNiemann-Pick type C: A disorder of cellular cholesterol trafficking
Introduction
Niemann-Pick disease was initially characterized by pathologic changes including hepatosplenomegaly, sphingomyelin storage in the reticuloendothelial and peripheral tissues, and neurodegeneration. In 1958 Crocker and Farber classified this heterogeneous group of diseases into Niemann-Pick groups A to D based on biochemical and clinical criteria [1]. Niemann-Pick groups A and B were subsequently shown to have a generalized sphingomyelinase deficiency [2], whereas groups C and D have normal sphingomyelinase levels [3]. A major step towards understanding the cellular lesion in Niemann-Pick groups C and D came from the study of a strain of BALB/c mice with neurovisceral lipidosis. The identification in this murine model of a lesion in the processing of exogenous cholesterol, and the biochemical similarities with human Niemann-Pick type C (NPC) disease led to our current understanding of NPC as a cholesterol storage disorder [4]. More recently, genetic studies have led to the isolation of the major disease gene, NPC1 [5]. The cloning of NPC1 has presented us with a new challenge to understand the biological function of the NPC1 protein and the molecular basis of NPC disease.
In this review the clinical manifestations and genetics of NPC disease, and the cellular consequences of the NPC lesion are discussed. The structure and cellular function of the NPC1 protein and its role in intracellular trafficking of cholesterol and sterol homeostasis are reviewed. Finally, the clinical implications of the recent advances in the study of NPC and future directions for research are discussed.
Section snippets
Clinical manifestations
The ‘classic’ NPC patient presents in early childhood with ataxia and progressive dementia. The neurologic hallmark of this disease is vertical supranuclear ophthalmoplegia, and this finding is present in almost all patients with late infantile or juvenile onset [6]. Other prominent neurologic features include cataplexy, dysarthria, dysphagia, dystonia and seizures. Hepatosplenomegaly is usually detected during early childhood. Children diagnosed with NPC experience increasing physical
Genetics of NPC disease
NPC is an inherited autosomal recessive disorder that affects diverse ethnic groups. The frequency of NPC in the general population has been estimated at approx. 1 in 100 000 live births, but the true incidence has been difficult to ascertain due to the limited availability of specific biochemical tests and the clinical heterogeneity of the disease [8]. However, in geographically isolated populations the prevalence of the disease is much higher. Among the French Acadians in Nova Scotia, the
Biochemical phenotype of NPC
NPC is a complex lipid storage disease characterized by the presence of visceral foamy cells and neuronal storage [6]. The liver and spleen accumulate unesterified cholesterol, sphingomyelin, bis(monoacylglycero)phosphate, neutral and acidic glycosphingolipids, and phospholipids. In contrast, the brain exhibits marked accumulation of glucosylceramide and lactosylceramide, as well as milder elevations in GM2 and GM3 gangliosides, but normal levels of cholesterol and sphingomyelin. Several
Structure of the NPC1 protein
A major advance towards understanding the cellular basis of NPC disease came from identification of the major disease gene, NPC1. The NPC1 gene and its murine orthologue were identified by positional cloning methods [5], [33]. The structure of the NPC1 protein is shown in Fig. 2. The 1278 amino acid human NPC1 protein has 13–16 predicted membrane spanning domains, five of which share sequence homology with the putative sterol sensing domains (SSD) of 3-hydroxy-3-methylglutaryl (HMG)-CoA
Implications for therapy in NPC
Based on our current understanding of the cellular lesion in NPC, pharmacologic approaches are being evaluated for treatment of this disease. Inhibitors of glycosphingolipid (GSL) biosynthesis, such as N-butyldeoxynojirimycin (NB-DNJ) and related compounds, have been shown in animal models of GSL storage diseases to be effective in depletion of neuronal GSL [53]. NB-DNJ is currently in clinical trials for treatment of type 1 Gaucher’s disease [54] and will be evaluated in upcoming clinical
Conclusion
The discovery of the NPC1 gene has brought us a step closer to understanding the pathogenesis of NPC disease. Identification of NPC1 has allowed the development of molecular tools to study the cellular function of NPC1. Specific antibodies raised against NPC1 sequences have localized the NPC1 protein to the late endocytic pathway. The subcellular distribution of NPC1 is also being examined using NPC1-GFP fusion proteins to study trafficking of the NPC1 protein in vivo. Sequence analysis of NPC1
Acknowledgements
I thank Jean Schaffer for her careful review of the manuscript. Work on NPC in the Ory lab has been supported by the National Niemann-Pick Disease Foundation.
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