Pathophysiology

Roles of NPC Gene Products in Pathogenesis

Research is ongoing to establish how NPC1 and NPC2 gene products are involved in the pathogenesis of lipid trafficking defects.⁷ The NPC1 gene product is a 1278 amino-acid protein (molecular weight 142 kDa) with 13 transmembrane domains.^1,8 It resides in the late-endosomal compartment, and is shuttled between this late-endosomal compartment and the plasma membrane, as well as other intracellular sites (Figure 5).^5,8 Its function is not yet clear, but it clearly plays an important role in the intracellular 'sorting' of cholesterol and glycosphingolipids (Figure 5).^7–11

The NPC2 protein is a soluble 132-amino acid glycoprotein that is expressed in all tissues, with the highest concentrations being found in epididymal fluid. NPC2 protein binds cholesterol in the luminal space of the late-endosome/lysosome and transports it to the delimiting membrane.^2,3,5

Figure 5. Alternative models for the role of NPC1 protein in cholesterol transport in NPC

Click image for larger version.

Illustration showing possible affected lipid trafficking pathways in NPC. LDL, low-density liproprotein; LR, LDL receptor; Tf, transferrin; TR, transferrin receptor. A number of researchers have suggested that NPC1 and NPC2 proteins may act co-operatively within the scheme of cellular lipid trafficking, for instance in intracellular sterol homeostasis.^12–14 However, it is currently not clear how the activities of these two proteins are co-ordinated, or how their activity is regulated in relation to the presence and concentration of cellular lipids.¹³

Other possible pathogenetic mechanisms

Further to the Alzheimer-like neuropathologic features seen in NPC46,55 (see Figure 4), links between pathogenetic mechanisms in NPC and Alzheimer’s disease have been suggested by studies at the molecular–genetic level.^6,15–18 In vitro data indicate that endosomal abnormalities related to impaired lipid trafficking in NPC may contribute to abnormal processing of amyloid precursor protein (APP) and aggregation of amyloidogenic protein fragments (e.g., beta-amyloid) in certain areas of the brain.^16,17

Analyses of genome-wide expression patterns have identified a number of changes in the expression of genes from NPC1 mutant fibroblasts that are also seen in Alzheimer’s disease.¹⁸ Many genes involved in the trafficking and processing of APP and the microtubule-associated protein, tau, were more highly expressed in NPC1 cells, as were a number of genes involved in membrane trafficking, intracellular regulation of calcium and metal ion levels and antioxidant capacity. While there seems to be a link between late-endosomal cholesterol accumulation and amyloid protein aggregation,¹⁹ the precise details of this interaction are not yet known. Nevertheless, Alzheimerassociated protein aggregation is considered a likely contributor to neurodegeneration in NPC.

Most recently, in vitro studies have shown that cellular autophagy is increased in NPC.^20,21 Autophagy in NPC1 mutant cells has been linked to increased expression of beclin-1 which, in turn, is related to impaired cholesterol trafficking. Interestingly, similar findings have been shown in NPC2 mutant cells as well as cells from Sandhoff disease mice. Together, these findings suggest that autophagy may also be a relevant neurodegenerative process in NPC.^20,21

References:
1. Patterson MC, Vanier MT, Suzuki K et al. Niemann–Pick disease, type C: a lipid traffi cking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th ed, 2001. New York: McGraw-Hill, Ch 145, pp 3611–33.
2. Chikh K, Vey S, Simonot C et al. Niemann–Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Mol Genet Metab 2004;83:220–30.
3. Chikh K, Rodriguez C, Vey S et al. Niemann–Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. Hum Mutat 2005;26:20–8.
4. Klünemann HH, Elleder M, Kaminski WE et al. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol 2002;52:743–9.
5. Mukherjee S, Maxfield FR. Lipid and cholesterol trafficking in NPC. Biochim Biophys Acta 2004;1685:28– 37.
6. Suzuki K, Parker CC, Pentchev PG et al. Neurofi brillary tangles in Niemann–Pick disease type C. Acta Neuropathol (Berl) 1995;89:227–38.
7. Sturley SL, Patterson MC, Balch W, Liscum L. The pathophysiology and mechanisms of NP-C disease. Biochim Biophys Acta 2004;1685:83–7.
8. Neufeld EB, Wastney M, Patel S et al. The Niemann–Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem 1999;274:9627–35.
9. Watari H, Blanchette-Mackie EJ, Dwyer NK et al. Niemann–Pick C1 protein: obligatory roles for N-terminal domains and lysosomal targeting in cholesterol mobilization. Proc Natl Acad Sci USA 1999;96:805–10.
10. Wojtanik KM, Liscum L. The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem 2003;278:14850–6.
11. Millard EE, Gale SE, Dudley N et al. The sterol-sensing domain of the Niemann–Pick C1 (NPC1) protein regulates trafficking of low density lipoprotein cholesterol. J Biol Chem 2005;280:28581–90.
12. Strauss JF, Liu P, Christenson LK, Watari H. Sterols and intracellular vesicular trafficking: lessons from the study of NPC1. Steroids 2002;67:947–51.
13. Liscum L, Sturley SL. Intracellular trafficking of Niemann–Pick C proteins 1 and 2: obligate components of subcellular lipid transport. Biochim Biophys Acta 2004;1685:22–7.
14. Frolov A, Zielinski SE, Crowley JR et al. NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. J Biol Chem 2003;278:25517–25.
15. Saito Y, Suzuki K, Nanba E et al. Niemann–Pick type C disease: accelerated neurofibrillary tangle formation and amyloid beta deposition associated with apolipoprotein E epsilon 4 homozygosity. Ann Neurol 2002;52:351–5.
16. Jin LW, Shie FS, Maezawa I et al. Intracellular accumulation of amyloidogenic fragments of amyloid-beta
precursor protein in neurons with Niemann–Pick type C defects is associated with endosomal abnormalities. Am J Pathol 2004;164:975–85.
17. Nixon RA. Niemann–Pick Type C disease and Alzheimer’s disease: the APP-endosome connection fattens up. Am J Pathol 2004;164:757–61.
18. Reddy JV, Ganley IG, Pfeffer SR. Clues to neuro-degeneration in Niemann–Pick type C disease from global gene expression profi ling. PLoS ONE 2006;1:e19.
19. Yamazaki T, Chang TY, Haass C, Ihara Y. Accumulation and aggregation of amyloid beta-protein in late endosomes of Niemann–Pick type C cells. J Biol Chem 2001;276:4454–60.
20. Pacheco CD, Kunkel R, Lieberman AP. Autophagy in Niemann–Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 2007;16:1495–503.
21. Pacheco CD, Lieberman AP. Lipid trafficking defects increase beclin-1 and activate autophagy in Niemann– Pick Type C disease. Autophagy 2007 Jun 14: [Epub ahead of print].

Niemann-Pick Knowledge Centre
(Type C)