Cellular pathology of Niemann–Pick type C disease

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Abstract

Niemann–Pick type C (NPC) is a lysosomal storage disorder that results in the accumulation of cholesterol and sphingolipids. Mutations in the NPC1 or NPC2 gene are responsible for the disease but the precise functions of the encoded proteins remain unresolved. Recent observations have challenged the traditional concept of NPC as a primary cholesterol transport defect. This review updates the recent NPC literature, summarizing the increasing insight into the cholesterol trafficking circuits and also addressing the contribution of other lipids in the cellular pathogenesis. The importance of NPC as a model for subcellular lipid imbalance in studying more common diseases, such as Alzheimer’s and cardiovascular diseases, is discussed.

Section snippets

Niemann–Pick type C disease phenotype

Niemann–Pick type C (NPC) is an autosomally, recessively inherited lysosomal storage disorder with a progressive and eventually fatal neurodegenerative course [1]. It belongs to the Niemann–Pick group of lipidoses along with Niemann–Pick types A and B. Types A and B are acid sphingomyelinase deficiencies whereas type C has been classified as a cholesterol transport defect [2]. NPC accounts for a bigger portion of Niemann–Pick disease patients than types A and B together and its prevalence has

Diagnostic principles of NPC

The classical biochemical manifestation of NPC is a failure of cells to esterify exogenously added cholesterol [2] as well as the accumulation of free (i.e. unesterified) cholesterol in the endo/lysosomal compartment and the Golgi apparatus [4]. The cells hydrolyze low density lipoprotein (LDL)-derived cholesterol esters normally but the homeostatic responses normally following cholesterol uptake, namely downregulation of LDL receptors and cholesterol synthesis fail, indicating defects in the

Defects in the NPC1 or NPC2 protein underlie NPC disease

NPC is also genetically heterogeneous as two complementation groups exist [12]. Both genes behind the disease have now been characterized. The NPC1 gene was identified by positional cloning in 1997 as the gene mutated in the major complementation group [13]. Three years later it was shown that the gene defective in the minor group was HE1/NPC2 [14]. Both genes are conserved during evolution, including organisms in which cholesterol is not a major building block of membranes (Table 1). NPC1

Cholesterol trafficking circuits perturbed in NPC

The loss of NPC1 or NPC2 function results in a multifaceted cellular pathology which has evoked diverse and partially discordant views of the primary lesion. Unlike several other lipidoses that result from defective enzyme activity, NPC appears to represent a primary transport defect. It is evident that cholesterol homeostasis in NPC cells has failed but whether the cholesterol transport defect is the primary problem or potentially a phenomenon secondary to some other malfunction (such as the

Vesicular trafficking in NPC

The role of vesicular transport in endocytic cholesterol trafficking has been extensively studied. The classical endocytic pathway mediating the transport of LDL particles to the hydrolytic organelles is well established [58]. The consensus is that the particle is transported via vesicular trafficking to late endosomes and lysosomes where it is degraded and the cholesterol hydrolyzed from the cholesterol esters by acid lipase. Interestingly, the enzyme is enriched in earlier endocytic

Sphingolipid accumulation in NPC

In this issue, a more thorough account of the sphingolipidosis in the NPC brain is provided in the article by S. Walkley. In the following, we will introduce select cell biologically relevant concepts related to sphingolipidosis in NPC. The multitude and heterogeneity of storage material in NPC is best reflected in neuronal tissues where primary accumulation is not that of cholesterol but instead GM3 and GM2 gangliosides, glucosylceramide and lactosylceramide [7]. Thus, it has been proposed

Fatty acids and NPC

Recent observations have pointed to the possibility that the function of NPC1 is related to lipid transport/metabolism yet distinct from that of sterols or sphingolipids. In bacteria, membrane-targeted expression of NPC1 was shown to mediate the influx of fatty acids and acriflavine but not that of cholesterol or cholesterol esters [23]. While the function of NPC1 as a fatty acid pump has not been demonstrated in eukaryotic cells, it has been proposed that in acetyl-LDL loaded macrophages NPC1

Implications and future prospects

An imminent question for the NPC research community is how the functions of NPC1 and NPC2 are linked, which—although not certain—seems very likely based on the available information. Secondly, how do the NPC proteins integrate into the protein networks that govern cellular metabolic and trafficking routes and expand in number and complexity as we learn more about cellular proteomics? So far, the interaction of NPC2 with the M6P receptor is the only such interaction characterized. Studies in

Acknowledgements

This work was financially supported by the Ara Parseghian Medical Research Foundation, the Academy of Finland and Sigrid Juselius Foundation.

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