Hostname: page-component-8448b6f56d-gtxcr Total loading time: 0 Render date: 2024-04-19T00:30:34.771Z Has data issue: false hasContentIssue false
  • English
  • Français

The pathogenesis of Niemann–Pick type C disease: a role for autophagy?

Published online by Cambridge University Press:  10 September 2008

Chris D. Pacheco  and
Andrew P. Lieberman
Chris D. Pacheco
Affiliation:
Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA.
Andrew P. Lieberman*
Affiliation:
Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
*
*Corresponding author: Andrew P. Lieberman, Department of Pathology, University of Michigan Medical School, 3500 MSRB 1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA. Tel: +1 734 647 4623; Fax: +1 734 615 3441; E-mail: liebermn@umich.edu
Get access Rights & Permissions [Opens in a new window]

Abstract

Niemann–Pick type C disease (NPC) is a sphingolipid-storage disorder that results from inherited deficiencies of intracellular lipid-trafficking proteins, and is characterised by an accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. Patients with this disorder develop progressive neurological impairment that often begins in childhood, is ultimately fatal and is currently untreatable. How impaired lipid trafficking leads to neurodegeneration is largely unknown. Here we review NPC clinical features and biochemical defects, and discuss model systems used to study this disorder. Recent studies have established that NPC is associated with an induction of autophagy, a regulated and evolutionarily conserved process by which cytoplasmic proteins are sequestered within autophagosomes and targeted for degradation. This pathway enables recycling of limited or damaged macromolecules to promote cell survival. However, in other instances, robust activation of autophagy leads to cell stress and programmed cell death. We summarise evidence showing that autophagy induction and flux are increased in NPC by signalling through a complex of the class III phosphoinositide 3-kinase and beclin-1. We propose that an imbalance between induction and flux through the autophagic pathway contributes to cell stress and neuronal loss in NPC and related sphingolipid-storage disorders, and discuss potential therapeutic strategies for modulating activity of this pathway.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 10 , October 2008 , e26
Copyright
Copyright © Cambridge University Press 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Meikle, P.J. et al. (1999) Prevalence of lysosomal storage disorders. JAMA 281, 249-254Google Scholar
2German, D.C. et al. (2002) Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109, 437-450CrossRefGoogle ScholarPubMed
3Patel, S.C. et al. (1999) Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann-Pick type C disease. Proc Natl Acad Sci U S A 96, 1657-1662CrossRefGoogle ScholarPubMed
4Vanier, M.T. and Millat, G. (2003) Niemann-Pick disease type C. Clin Genet 64, 269-281Google Scholar
5Higgins, J.J. et al. (1992) A clinical staging classification for type C Niemann-Pick disease. Neurology 42, 2286-2290Google Scholar
6Karten, B. et al. (2002) Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J Neurochem 83, 1154-1163CrossRefGoogle ScholarPubMed
7Karten, B. et al. (2003) Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons. J Biol Chem 278, 4168-4175Google Scholar
8Reid, P.C., Sugii, S. and Chang, T.Y. (2003) Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice. J Lipid Res 44, 1010-1019CrossRefGoogle ScholarPubMed
9Carstea, E.D. et al. (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228-231CrossRefGoogle ScholarPubMed
10Naureckiene, S. et al. (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298-2301CrossRefGoogle ScholarPubMed
11Patterson, M.C. et al. (2001) Niemann-Pick disease type C: a lipid trafficking disorder. In The Metabolic and Molecular Bases of Inherited Disease (8th edn), pp. 3611-3634, McGraw-Hill, New YorkGoogle Scholar
12Yamamoto, T. et al. (2000) Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts. J Med Genet 37, 707-712Google Scholar
13Imrie, J. et al. (2002) Niemann-Pick disease type C in adults. J Inherit Metab Dis 25, 491-500CrossRefGoogle ScholarPubMed
14Turpin, J.C., Masson, M. and Baumann, N. (1991) Clinical aspects of Niemann-Pick type C disease in the adult. Dev Neurosci 13, 304-306CrossRefGoogle ScholarPubMed
15Vanier, M.T. et al. (1988) Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients. Clin Genet 33, 331-348Google Scholar
16Sevin, M. et al. (2007) The adult form of Niemann-Pick disease type C. Brain 130, 120-133CrossRefGoogle ScholarPubMed
17Millat, G. et al. (2001) Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 69, 1013-1021CrossRefGoogle ScholarPubMed
18Walkley, S.U. and Suzuki, K. (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 1685, 48-62Google Scholar
19Auer, I.A. et al. (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease. Acta Neuropathol 90, 547-551Google Scholar
20Dietschy, J.M. and Turley, S.D. (2002) Control of cholesterol turnover in the mouse. J Biol Chem 277, 3801-3804Google Scholar
21Quan, G. et al. (2003) Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res Dev Brain Res 146, 87-98Google Scholar
22Herz, J. and Bock, H.H. (2002) Lipoprotein receptors in the nervous system. Annu Rev Biochem 71, 405-434CrossRefGoogle ScholarPubMed
23Turley, S.D. et al. (1996) Brain does not utilize low density lipoprotein-cholesterol during fetal and neonatal development in the sheep. J Lipid Res 37, 1953-1961Google Scholar
24Dietschy, J.M. and Turley, S.D. (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12, 105-112CrossRefGoogle ScholarPubMed
25Mauch, D.H. et al. (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354-1357CrossRefGoogle ScholarPubMed
26Pagano, R.E. (2003) Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases. Philos Trans R Soc Lond B Biol Sci 358, 885-891Google Scholar
27Fu, X. et al. (2001) 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276, 38378-38387Google Scholar
28Janowski, B.A. et al. (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728-731CrossRefGoogle ScholarPubMed
29Ory, D.S. (2000) Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta 1529, 331-339Google Scholar
30Liscum, L., Ruggiero, R.M. and Faust, J.R. (1989) The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J Cell Biol 108, 1625-1636Google Scholar
31Sokol, J. et al. (1988) Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol. J Biol Chem 263, 3411-3417Google Scholar
32Wojtanik, K.M. and Liscum, L. (2003) The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem 278, 14850-14856CrossRefGoogle Scholar
33Vance, J.E. (2006) Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett 580, 5518-5524Google Scholar
34Thomas, G.H. et al. (1989) Correction of sphingomyelinase deficiency in Niemann-Pick type C fibroblasts by removal of lipoprotein fraction from culture media. J Inherit Metab Dis 12, 139-151Google Scholar
35Higgins, M.E. et al. (1999) Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. Mol Genet Metab 68, 1-13Google Scholar
36Neufeld, E.B. et al. (1999) The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem 274, 9627-9635Google Scholar
37Watari, H. et al. (1999) Mutations in the leucine zipper motif and sterol-sensing domain inactivate the Niemann-Pick C1 glycoprotein. J Biol Chem 274, 21861-21866Google Scholar
38Runz, H. et al. (2008) NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat 29, 345-350CrossRefGoogle ScholarPubMed
39Malathi, K. et al. (2004) Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution. J Cell Biol 164, 547-556Google Scholar
40Sym, M., Basson, M. and Johnson, C. (2000) A model for niemann-pick type C disease in the nematode Caenorhabditis elegans. Curr Biol 10, 527-530Google Scholar
41Huang, X. et al. (2005) A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis. Development 132, 5115-5124Google Scholar
42Pentchev, P.G. et al. (1986) The cholesterol storage disorder of the mutant BALB/c mouse. A primary genetic lesion closely linked to defective esterification of exogenously derived cholesterol and its relationship to human type C Niemann-Pick disease. J Biol Chem 261, 2772-2777Google Scholar
43Brown, D.E. et al. (1994) Feline Niemann-Pick disease type C. Am J Pathol 144, 1412-1415Google ScholarPubMed
44Kuwamura, M. et al. (1993) Type C Niemann-Pick disease in a boxer dog. Acta Neuropathol 85, 345-348Google Scholar
45Mutka, A.L. et al. (2004) Secretion of sterols and the NPC2 protein from primary astrocytes. J Biol Chem 279, 48654-48662Google Scholar
46Friedland, N. et al. (2003) Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc Natl Acad Sci U S A 100, 2512-2517Google Scholar
47Ko, D.C. et al. (2003) The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels. Proc Natl Acad Sci U S A 100, 2518-2525CrossRefGoogle ScholarPubMed
48Sleat, D.E. et al. (2004) Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A 101, 5886-5891Google Scholar
49Loftus, S.K. et al. (1997) Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232-235Google Scholar
50Morris, M.D. et al. (1982) Lysosome lipid storage disorder in NCTR-BALB/c mice. I. Description of the disease and genetics. Am J Pathol 108, 140-149Google Scholar
51Rimkunas, V.M. et al. (2008) In vivo antisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease. Hepatology 47, 1504-1512CrossRefGoogle ScholarPubMed
52Walkley, S.U. (1995) Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside immunoreactivity. Neuroscience 68, 1027-1035Google Scholar
53Xie, C. et al. (2000) Cholesterol is sequestered in the brains of mice with Niemann-Pick type C disease but turnover is increased. J Neuropathol Exp Neurol 59, 1106-1117Google Scholar
54Zervas, M., Dobrenis, K. and Walkley, S.U. (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, 49-64Google Scholar
55Takikita, S. et al. (2004) Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J Neuropathol Exp Neurol 63, 660-673CrossRefGoogle ScholarPubMed
56Higashi, Y. et al. (1993) Cerebellar degeneration in the Niemann-Pick type C mouse. Acta Neuropathol 85, 175-184Google Scholar
57Yu, W. et al. (2005) Neurodegeneration in heterozygous Niemann-Pick type C1 (NPC1) mouse: implication of heterozygous NPC1 mutations being a risk for tauopathy. J Biol Chem 280, 27296-27302Google Scholar
58Gondre-Lewis, M.C., McGlynn, R. and Walkley, S.U. (2003) Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr Biol 13, 1324-1329CrossRefGoogle ScholarPubMed
59Cox, T. et al. (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355, 1481-1485Google Scholar
60Zervas, M. et al. (2001) Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol 11, 1283-1287CrossRefGoogle ScholarPubMed
61Patterson, M.C. et al. (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6, 765-772Google Scholar
62Mellon, S.H. (2007) Neurosteroid regulation of central nervous system development. Pharmacol Ther 116, 107-124Google Scholar
63Griffin, L.D. et al. (2004) Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10, 704-711Google Scholar
64Langmade, S.J. et al. (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci U S A 103, 13807-13812CrossRefGoogle Scholar
65Frolov, A. et al. (2001) Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. J Biol Chem 276, 46414-46421CrossRefGoogle ScholarPubMed
66Repa, J.J. et al. (2007) Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse. J Neurosci 27, 14470-14480Google Scholar
67Ko, D.C. et al. (2005) Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. PLoS Genet 1, 81-95Google ScholarPubMed
68Mizushima, N. et al. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075Google Scholar
69Klionsky, D.J. et al. (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5, 539-545CrossRefGoogle ScholarPubMed
70Xie, Z. and Klionsky, D.J. (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9, 1102-1109CrossRefGoogle ScholarPubMed
71Ohsumi, Y. and Mizushima, N. (2004) Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol 15, 231-236CrossRefGoogle ScholarPubMed
72Kabeya, Y. et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 5720-5728Google Scholar
73Tanida, I., Ueno, T. and Kominami, E. (2004) Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met121 to expose Gly120 for lipidation and targeting to autophagosomal membranes. J Biol Chem 279, 47704-47710CrossRefGoogle ScholarPubMed
74Tanida, I. et al. (2005) Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1, 84-91CrossRefGoogle Scholar
75Klionsky, D.J. and Emr, S.D. (2000) Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721Google Scholar
76Noda, T. and Ohsumi, Y. (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273, 3963-3966Google Scholar
77Yamamoto, A., Cremona, M.L. and Rothman, J.E. (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172, 719-731Google Scholar
78Nixon, R.A. (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120, 4081-4091Google Scholar
79Pan, T. et al. (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease. Brain, Jan 10 [Epub ahead of print]Google Scholar
80Ravikumar, B. et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36, 585-595Google Scholar
81Kiselyov, K. et al. (2007) Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy 3, 259-262CrossRefGoogle ScholarPubMed
82Williams, A. et al. (2006) Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. Curr Top Dev Biol 76, 89-101Google Scholar
83Kuma, A. et al. (2004) The role of autophagy during the early neonatal starvation period. Nature 432, 1032-1036CrossRefGoogle ScholarPubMed
84Komatsu, M. et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884Google Scholar
85Shimizu, S. et al. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6, 1221-1228Google Scholar
86Shintani, T. and Klionsky, D.J. (2004) Autophagy in health and disease: a double-edged sword. Science 306, 990-995Google Scholar
87Liao, G. et al. (2007) Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1−/−mouse brain. Am J Pathol 171, 962-975Google Scholar
88Pacheco, C.D., Kunkel, R. and Lieberman, A.P. (2007) Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 16, 1495-1503Google Scholar
89Cheng, J. et al. (2006) Cholesterol depletion induces autophagy. Biochem Biophys Res Commun 351, 246-252CrossRefGoogle ScholarPubMed
90Lajoie, P. et al. (2005) The lipid composition of autophagic vacuoles regulates expression of multilamellar bodies. J Cell Sci 118, 1991-2003Google Scholar
91Levine, B. and Kroemer, G. (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42Google Scholar
92Raben, N., Roberts, A. and Plotz, P.H. (2007) Role of autophagy in the pathogenesis of Pompe disease. Acta Myol 26, 45-48Google Scholar
93Vergarajauregui, S. et al. (2008) Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet, Jun 11 (Epub ahead of print]Google Scholar
94Settembre, C. et al. (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17, 119-129CrossRefGoogle ScholarPubMed
95Cao, Y. et al. (2006) Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem 281, 20483-20493Google Scholar
96Beck, M. (2007) New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 121, 1-22Google Scholar
97Hsu, Y.S. et al. (1999) Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant 24, 103-107Google Scholar
98Escolar, M.L. et al. (2005) Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 352, 2069-2081Google Scholar
99Patterson, M.C. et al. (1993) The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology 43, 61-64Google Scholar
100Sylvain, M. et al. (1994) Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin. Pediatr Neurol 10, 228-232Google Scholar
101Jeyakumar, M. et al. (2001) Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation. Blood 97, 327-329Google Scholar
102Gaumann, A., Schlitt, H.J. and Geissler, E.K. (2008) Immunosuppression and tumor development in organ transplant recipients: the emerging dualistic role of rapamycin. Transpl Int 21, 207-217Google Scholar

Further reading, resources and contacts

There are several excellent recent reviews on autophagy and disease, including:

The Ara Parseghian Medical Research Foundation supports scientific research on Niemann–Pick type C disease and related disorders. Their website includes information about the Foundation, the diseases they target with research support, and links to other sources of information:

Levine, B. and Kroemer, G. (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42Google Scholar
Mizushima, N. et al. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075Google Scholar
www.parseghian.orgGoogle Scholar
www.nnpdf.orgGoogle Scholar
Levine, B. and Kroemer, G. (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42Google Scholar
Mizushima, N. et al. (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075Google Scholar
www.parseghian.orgGoogle Scholar
www.nnpdf.orgGoogle Scholar