Abstract
Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".
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Amraoui Y, Mengel E, Hennermann JB (2014) Oxysterols in Niemann-Pick type C: limitations of sensitivity and specificity. J Inherit Metab Dis 37(suppl):S150, abstract
Aqul A, Liu B, Ramirez CM et al (2011) Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J Neurosci 31:9404–9413
Bergamin N, Dardis A, Beltrami A et al (2013) A human neuronal model of Niemann Pick C disease developed from stem cells isolated from patient's skin. Orphanet J Rare Dis 8:34
Björkhem I, Diczfalusy U, Lövgren-Sandblom A et al (2014) On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO. J Lipid Res 55:1165–1172
Blom T, Li Z, Bittman R, Somerharju P, Ikonen E (2012) Tracking sphingosine metabolism and transport in sphingolipidoses: NPC1 deficiency as a test case. Traffic 13:1234–1243
Boenzi S, Deodato F, Taurisano R et al (2014) A new simple and rapid LC-ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann-Pick type C disease. Clin Chim Acta 437:93–100
Carstea ED, Morris JA, Coleman KG et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277:228–231
Chevallier J, Chamoun Z, Jiang G et al (2008) Lysobisphosphatidic acid controls endosomal cholesterol levels. J Biol Chem 283:27871–27880
Choudhury A, Sharma DK, Marks DL, Pagano RE (2004) Elevated endosomal cholesterol levels in Niemann-Pick cells inhibit rab4 and perturb membrane recycling. Mol Biol Cell 15:4500–4511
Davidson CD, Ali NF, Micsenyi MC et al (2009) Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4:e6951
Deffieu MS, Pfeffer SR (2011) Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding. Proc Natl Acad Sci U S A 108:18932–18936
Devlin C, Pipalia NH, Liao X, Schuchman EH, Maxfield FR, Tabas I (2010) Improvement in lipid and protein trafficking in Niemann-Pick C1 cells by correction of a secondary enzyme defect. Traffic 11:601–615
Elrick MJ, Lieberman AP (2013) Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis. Autophagy 9:234–235
Fan M, Sidhu R, Fujiwara H et al (2013) Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling. J Lipid Res 54:2800–2814
Gallala HD, Breiden B, Sandhoff K (2011) Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. J Neurochem 116:702–707
Gelsthorpe ME, Baumann N, Millard E et al (2008) Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding. J Biol Chem 283:8229–8236
Goldin E, Roff CF, Miller SP et al (1992) Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver. Biochim Biophys Acta 1127:303–311
Goldman SD, Krise JP (2010) Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo. J Biol Chem 285:4983–4994
Higgins ME, Davies JP, Chen FW, Ioannou YA (1999) Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab 68:1–13
Jiang H, Sidhu R, Fujiwara H et al (2014) Development and validation of sensitive LC-MS/MS assays for quantification of 2-hydroxypropyl-beta-cyclodextrin in human plasma and CSF. J Lipid Res 55:1537–1548
Karten B, Vance DE, Campenot RB, Vance JE (2002) Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J Neurochem 83:1154–1163
Kennedy BE, Charman M, Karten B (2012) Niemann-Pick Type C2 protein contributes to the transport of endosomal cholesterol to mitochondria without interacting with NPC1. J Lipid Res 53:2632–2642
Kennedy BE, Madreiter CT, Vishnu N, Malli R, Graier WF, Karten B (2014) Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient Cells. J Biol Chem 289:16278–16289
Kolter T, Sandhoff K (2010) Lysosomal degradation of membrane lipids. FEBS Lett 584:1700–1712
Kruth HS, Comly ME, Butler JD et al (1986) Type C Niemann-Pick disease. Abnormal metabolism of low density lipoprotein in homozygous and heterozygous fibroblasts. J Biol Chem 261:16769–16774
Kwon HJ, Abi-Mosleh L, Wang ML et al (2009) Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137:1213–1224
Ledesma MD, Prinetti A, Sonnino S, Schuchman EH (2011) Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice. J Neurochem 116:779–788
Li H, Turley SD, Liu B, Repa JJ, Dietschy JM (2008) GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice. J Lipid Res 49:1816–1828
Lieberman AP, Puertollano R, Raben N, Slaugenhaupt S, Walkley SU, Ballabio A (2012) Autophagy in lysosomal storage disorders. Autophagy 8:719–730
Lin N, Zhang H, Qiu W et al (2014) Determination of 7-ketocholesterol in plasma by liquid chromatography mass spectrometry for rapid diagnosis of acid sphingomyelinase deficient Niemann-Pick disease. J Lipid Res 55:338–343
Liu Y, Wu YP, Wada R et al (2000) Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse. Hum Mol Genet 9:1087–1092
Lloyd-Evans E, Morgan AJ, He X et al (2008) Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med 14:1247–1255
Lopez ME, Klein AD, Dimbil UJ, Scott MP (2011) Anatomically defined neuron-based rescue of neurodegenerative Niemann-Pick type C disorder. J Neurosci 31:4367–4378
Maetzel D, Sarkar S, Wang H et al (2014) Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cells derived from Niemann-Pick type C patient-specific iPS cells. Stem Cell Rep 2:866–880
Maue RA, Burgess RW, Wang B et al (2012) A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Hum Mol Genet 21:730–750
Mazière JC, Mazière C, Gardette J, Mora L, Polonovski J (1981) Changes in cholesterol metabolism in cultured fibroblasts from patients with Niemann-Pick disease. Biochem Biophys Res Commun 102:113–118
Miller EH, Obernosterer G, Raaben M, et al (2012) Ebola virus entry requires the host-programmed recognition of an intracellular receptor. EMBO J 31:1947–1960
Naureckiene S, Sleat DE, Lackland H et al (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290:2298–2301
Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea ED, Neufeld EB, Blanchette-Mackie EJ, Pentchev PG (2001) Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease. Mc Graw Hill, New York, pp 3611–3634
Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F (2012) Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab 106:330–344
Patterson MC, Mengel E, Wijburg FA et al (2013) Disease and patient characteristics in NP-C patients: findings from an international disease registry. Orphanet J Rare Dis 8:12
Pentchev PG, Gal AE, Booth AD et al (1980) A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase. Biochim Biophys Acta 619:669–679
Pentchev PG, Comly ME, Kruth HS et al (1987) Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J 1:40–45
Philippart M, Martin L, Martin JJ, Menkes JH (1969) Niemann-Pick disease. Morphologic and biochemical studies in the visceral form with late central nervous system involvement (Crocker's group C). Arch Neurol 20:227–238
Platt FM, Wassif C, Colaco A et al (2014) Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease. Annu Rev Genomics Hum Genet 15:173–194
Poirier S, Mayer G, Murphy SR et al (2013) The cytosolic adaptor AP-1A is essential for the trafficking and function of Niemann-Pick type C proteins. Traffic 14:458–469
Porter FD, Scherrer DE, Lanier MH et al (2010) Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med 2:56ra81
Puri V, Watanabe R, Dominguez M et al (1999) Cholesterol modulates membrane traffic along the endocytic pathway in sphingolipid-storage diseases. Nat Cell Biol 1:386–388
Reagan JW Jr, Hubbert ML, Shelness GS (2000) Posttranslational regulation of acid sphingomyelinase in Niemann-Pick type C1 fibroblasts and free cholesterol-enriched Chinese hamster ovary cells. J Biol Chem 275:38104–38110
Reid PC, Sakashita N, Sugii S et al (2004) A novel cholesterol stain reveals early neuronal cholesterol accumulation in the Niemann-Pick type C1 mouse brain. J Lipid Res 45:582–591
Ribeiro I, Marcao A, Amaral O et al (2001) Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Hum Genet 109:24–32
Rodriguez-Lafrasse C, Vanier MT (1999) Sphingosylphosphorylcholine in Niemann-Pick disease brain: accumulation in type A but not in type B. Neurochem Res 24:199–205
Rodriguez-Lafrasse C, Rousson R, Pentchev PG, Louisot P, Vanier MT (1994) Free sphingoid bases in tissues from patients with type C Niemann-Pick disease and other lysosomal storage disorders. Biochim Biophys Acta 1226:138–144
Rodriguez-Lafrasse C, Rousson R, Valla S et al (1997) Modulation of protein kinase C by endogenous sphingosine: inhibition of phorbol dibutyrate binding in Niemann-Pick C fibroblasts. Biochem J 325:787–791
Roff CF, Goldin E, Comly ME et al (1991) Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport. Dev Neurosci 13:315–319
Salvioli R, Scarpa S, Ciaffoni F et al (2004) Glucosylceramidase mass and subcellular localization are modulated by cholesterol in Niemann-Pick disease type C. J Biol Chem 279:17674–17680
Sarkar S, Carroll B, Buganim Y et al (2013) Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep 5:1302–1315
Sarkar S, Maetzel D, Korolchuk VI, Jaenisch R (2014) Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease. Autophagy 10:1137–1140
Sleat DE, Wiseman JA, El-Banna M et al (2004) Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A 101:5886–5891
Sleat DE, Wiseman JA, Sohar I et al (2012) Proteomic analysis of mouse models of Niemann-Pick C disease reveals alterations in the steady-state levels of lysosomal proteins within the brain. Proteomics 12:3499–3509
Spence MW, Callahan JW (1989) Sphingomyelin-cholesterol lipidoses: the Niemann-Pick group of diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1655–1676
Stein VM, Crooks A, Ding W et al (2012) Miglustat improves Purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J Neuropathol Exp Neurol 71:434–448
Storch J, Xu Z (2009) Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochim Biophys Acta 1791:671–678
Tamura H, Takahashi T, Ban N et al (2006) Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency. Mol Genet Metab 87:113–121
Thomas GH, Tuck-Muller CM, Miller CS, Reynolds LW (1989) Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media. J Inherit Metab Dis 12:139–151
Tjiong HB, Seng PN, Debuch H, Wiedemann HR (1973) Brain lipids of a case of juvenile Niemann-Pick disease. J Neurochem 21:1475–1485
van der Kant R, Zondervan I, Janssen L, Neefjes J (2013) Cholesterol binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1. J Lipid Res 54:2153–2165
Vance JE (2012) Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis Model Mech 5:746–755
Vance JE, Karten B (2014) Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin. J Lipid Res 55:1609–1621
Vanier MT (1983) Biochemical studies in Niemann-Pick disease. I. Major sphingolipids of liver and spleen. Biochim Biophys Acta 750:178–184
Vanier MT (1999) Lipid changes in Niemann-Pick disease type C brain: personal experience and review of the literature. Neurochem Res 24:481–489
Vanier MT (2010) Niemann-Pick disease type C. Orphanet J Rare Dis 5:16
Vanier MT, Latour P (2015) Laboratory diagnosis of Niemann-Pick type C: the filipin staining test. Meth Cell Biol, in press
Vanier MT, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64:269–281
Vanier MT, Patterson MC (2012) Niemann-Pick disese type C. In: Mehta A, Winchester B (eds) Lysosomal storage disorders. A practical guide. Wiley-Blackwell, Chichester, pp 87–93
Vanier MT, Suzuki K (1998) Recent advances in elucidating Niemann-Pick C disease. Brain Pathol 8:163–174
Vanier MT, Revol A, Fichet M (1980) Sphingomyelinase activities of various human tissues in control subjects and in Niemann-Pick disease - development and evaluation of a microprocedure. Clin Chim Acta 106:257–267
Vanier MT, Wenger DA, Comly ME, Rousson R, Brady RO, Pentchev PG (1988) Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients. Clin Genet 33:331–348
Vanier MT, Pentchev P, Rodriguez-Lafrasse C, Rousson R (1991a) Niemann-Pick disease type C: an update. J Inherit Metab Dis 14:580–595
Vanier MT, Rodriguez-Lafrasse C, Rousson R et al (1991b) Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing. Biochim Biophys Acta 1096:328–337
Vanier MT, Duthel S, Rodriguez-Lafrasse C, Pentchev P, Carstea ED (1996) Genetic heterogeneity in Niemann-Pick C disease: a study using somatic cell hybridization and linkage analysis. Am J Hum Genet 58:118–125
Vite C, Mauldin E, Ward S et al (2011) Intrathecal cyclodextrin therapy of feline Niemann-Pick type C disease. Mol Genet Metab 102:544
Walkley SU, Suzuki K (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 1685:48–62
Walkley SU, Vanier MT (2009) Secondary lipid accumulation in lysosomal disease. Biochim Biophys Acta 1793:726–736
Walter M, Chen FW, Tamari F, Wang R, Ioannou YA (2009) Endosomal lipid accumulation in NPC1 leads to inhibition of PKC, hypophosphorylation of vimentin and Rab9 entrapment. Biol Cell 101:141–152
Wang ML, Motamed M, Infante RE et al (2010) Identification of surface residues on Niemann-Pick C2 essential for hydrophobic handoff of cholesterol to NPC1 in lysosomes. Cell Metab 12:166–173
Weintraub H, Abramovici A, Sandbank U et al (1985) Neurological mutation characterized by dysmyelination in NCTR-Balb/C mouse with lysosomal lipid storage disease. J Neurochem 45:665–672
Willenborg M, Schmidt CK, Braun P et al (2005) Mannose 6-phosphate receptors, Niemann-Pick C2 protein, and lysosomal cholesterol accumulation. J Lipid Res 46:2559–2569
Wortmann SB, Vaz FM, Gardeitchik T et al (2012) Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet 44:797–802
Wraith JE, Sedel F, Pineda M et al (2014) Niemann-Pick type C Suspicion Index tool: analyses by age and association of manifestations. J Inherit Metab Dis 37:93–101
Xie X, Brown MS, Shelton JM, Richardson JA, Goldstein JL, Liang G (2011) Amino acid substitution in NPC1 that abolishes cholesterol binding reproduces phenotype of complete NPC1 deficiency in mice. Proc Natl Acad Sci U S A 108:15330–15335
Yu T, Lieberman AP (2013) Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin. PLoS Genet 9:e1003462
Yu T, Shakkottai VG, Chung C, Lieberman AP (2011) Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. Hum Mol Genet 20:4440–4451
Zervas M, Dobrenis K, Walkley SU (2001) Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 60:49–64
Zhang M, Sun M, Dwyer NK et al (2003) Differential trafficking of the Niemann-Pick C1 and 2 proteins highlights distinct roles in late endocytic lipid trafficking. Acta Paediatr Suppl 92:63–73, discussion 45
Zhang H, Wang Y, Lin N et al (2014) Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. Orphanet J Rare Dis 9:82
Zhou S, Davidson C, McGlynn R et al (2011) Endosomal/lysosomal processing of gangliosides affects neuronal cholesterol sequestration in Niemann-Pick disease type C. Am J Pathol 179:890–902
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MTV has received travel expenses, consulting fees and presentation honoraria from Actelion Pharmaceuticals Ltd and consulting fees from Shire HGT
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Communicated by: Ronald J.A. Wanders
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Vanier, M.T. Complex lipid trafficking in Niemann-Pick disease type C. J Inherit Metab Dis 38, 187–199 (2015). https://doi.org/10.1007/s10545-014-9794-4
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DOI: https://doi.org/10.1007/s10545-014-9794-4