Skip to main content
    • Aa
    • Aa
  • Get access
    Check if you have access via personal or institutional login
  • Cited by 25
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Menzies, Fiona M. Fleming, Angeleen and Rubinsztein, David C. 2015. Compromised autophagy and neurodegenerative diseases. Nature Reviews Neuroscience, Vol. 16, Issue. 6, p. 345.

    Li, Y Li, S Qin, X Hou, W Dong, H Yao, L and Xiong, L 2014. The pleiotropic roles of sphingolipid signaling in autophagy. Cell Death and Disease, Vol. 5, Issue. 5, p. e1245.

    Seshan, S.V. and Barisoni, L. 2014. Pathobiology of Human Disease.

    Aki, Toshihiko Funakoshi, Takeshi Unuma, Kana and Uemura, Koichi 2013. Impairment of autophagy: From hereditary disorder to drug intoxication. Toxicology, Vol. 311, Issue. 3, p. 205.

    Boustany, Rose-Mary Al-Shareef, Ibraheem and El-Haddad, Sariah 2013. Emery and Rimoin's Principles and Practice of Medical Genetics.

    Poirier, Steve Mayer, Gaétan Murphy, Stephanie R. Garver, William S. Chang, Ta Yuan Schu, Peter and Seidah, Nabil G. 2013. The Cytosolic Adaptor AP-1A Is Essential for the Trafficking and Function of Niemann-Pick Type C Proteins. Traffic, Vol. 14, Issue. 4, p. 458.

    Ghavami, Saeid Cunnington, Ryan H. Yeganeh, Behzad Davies, Jared J.L. Rattan, Sunil G. Bathe, Krista Kavosh, Morvarid Los, Marek J. Freed, Darren H. Klonisch, Thomas Pierce, Grant N. Halayko, Andrew J. and Dixon, Ian M.C. 2012. Autophagy regulates trans fatty acid-mediated apoptosis in primary cardiac myofibroblasts. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 1823, Issue. 12, p. 2274.

    Maulik, M. Ghoshal, B. Kim, J. Wang, Y. Yang, J. Westaway, D. and Kar, S. 2012. Mutant human APP exacerbates pathology in a mouse model of NPC and its reversal by a  -cyclodextrin. Human Molecular Genetics, Vol. 21, Issue. 22, p. 4857.

    Ordonez, M. P. Roberts, E. A. Kidwell, C. U. Yuan, S. H. Plaisted, W. C. and Goldstein, L. S. B. 2012. Disruption and therapeutic rescue of autophagy in a human neuronal model of Niemann Pick type C1. Human Molecular Genetics, Vol. 21, Issue. 12, p. 2651.

    Salsano, Ettore Umeh, Chizoba Rufa, Alessandra Pareyson, Davide and Zee, David S. 2012. Vertical supranuclear gaze palsy in Niemann-Pick type C disease. Neurological Sciences, Vol. 33, Issue. 6, p. 1225.

    van Echten-Deckert, Gerhild and Walter, Jochen 2012. Sphingolipids: Critical players in Alzheimer’s disease. Progress in Lipid Research, Vol. 51, Issue. 4, p. 378.

    Vázquez, Mary Carmen Balboa, Elisa Alvarez, Alejandra R. and Zanlungo, Silvana 2012. Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease. Oxidative Medicine and Cellular Longevity, Vol. 2012, p. 1.

    Cianciola, Nicholas L. Carlin, Cathleen R. and Kelley, Thomas J. 2011. Molecular pathways for intracellular cholesterol accumulation: Common pathogenic mechanisms in Niemann–Pick disease Type C and cystic fibrosis. Archives of Biochemistry and Biophysics, Vol. 515, Issue. 1-2, p. 54.

    Jegga, Anil G. Schneider, Lonnie Ouyang, Xiaosen and Zhang, Jianhua 2011. Systems biology of the autophagy-lysosomal pathway. Autophagy, Vol. 7, Issue. 5, p. 477.

    Morris, Meaghan Maeda, Sumihiro Vossel, Keith and Mucke, Lennart 2011. The Many Faces of Tau. Neuron, Vol. 70, Issue. 3, p. 410.

    Paisán-Ruiz, Coro Parkkinen, Laura and Revesz, Tamas 2011. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders.

    Elrick, M. J. Pacheco, C. D. Yu, T. Dadgar, N. Shakkottai, V. G. Ware, C. Paulson, H. L. and Lieberman, A. P. 2010. Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Human Molecular Genetics, Vol. 19, Issue. 5, p. 837.

    Illsinger, Sabine and Das, Anibh M. 2010. Impact of selected inborn errors of metabolism on prenatal and neonatal development. IUBMB Life, p. n/a.

    Kim, Su Kang Park, Hae Jeong Lee, Jong Seok Park, Hyun-Kyung Jo, Dae Jean Kim, Dong Hwan Chung, Joo-Ho and Kim, Mi-Ja 2010. Association of Niemann-Pick disease, type C2 (NPC2) polymorphisms with obesity in Korean population. Molecular & Cellular Toxicology, Vol. 6, Issue. 4, p. 391.

    Kodam, A. Maulik, M. Peake, K. Amritraj, A. Vetrivel, K. S. Thinakaran, G. Vance, J. E. and Kar, S. 2010. Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains. Glia, Vol. 58, Issue. 11, p. 1267.

  • Expert Reviews in Molecular Medicine, Volume 10
  • 2008, e26

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

  • Chris D. Pacheco (a1) and Andrew P. Lieberman (a1) (a2)
  • DOI:
  • Published online: 01 September 2008

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.

Corresponding author
*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:
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1P.J. Meikle (1999) Prevalence of lysosomal storage disorders. JAMA 281, 249-254

2D.C. German (2002) Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 109, 437-450

3S.C. Patel (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, 1657-1662

4M.T. Vanier and G. Millat (2003) Niemann-Pick disease type C. Clin Genet 64, 269-281

5J.J. Higgins (1992) A clinical staging classification for type C Niemann-Pick disease. Neurology 42, 2286-2290

6B. Karten (2002) Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons. J Neurochem 83, 1154-1163

7B. Karten (2003) Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons. J Biol Chem 278, 4168-4175

8P.C. Reid , S. Sugii and T.Y. Chang (2003) Trafficking defects in endogenously synthesized cholesterol in fibroblasts, macrophages, hepatocytes, and glial cells from Niemann-Pick type C1 mice. J Lipid Res 44, 1010-1019

9E.D. Carstea (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277, 228-231

10S. Naureckiene (2000) Identification of HE1 as the second gene of Niemann-Pick C disease. Science 290, 2298-2301

12T. Yamamoto (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, 707-712

13J. Imrie (2002) Niemann-Pick disease type C in adults. J Inherit Metab Dis 25, 491-500

14J.C. Turpin , M. Masson and N. Baumann (1991) Clinical aspects of Niemann-Pick type C disease in the adult. Dev Neurosci 13, 304-306

16M. Sevin (2007) The adult form of Niemann-Pick disease type C. Brain 130, 120-133

17G. Millat (2001) Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 69, 1013-1021

18S.U. Walkley and K. Suzuki (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 1685, 48-62

19I.A. Auer (1995) Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer's disease. Acta Neuropathol 90, 547-551

20J.M. Dietschy and S.D. Turley (2002) Control of cholesterol turnover in the mouse. J Biol Chem 277, 3801-3804

21G. Quan (2003) Ontogenesis and regulation of cholesterol metabolism in the central nervous system of the mouse. Brain Res Dev Brain Res 146, 87-98

22J. Herz and H.H. Bock (2002) Lipoprotein receptors in the nervous system. Annu Rev Biochem 71, 405-434

24J.M. Dietschy and S.D. Turley (2001) Cholesterol metabolism in the brain. Curr Opin Lipidol 12, 105-112

25D.H. Mauch (2001) CNS synaptogenesis promoted by glia-derived cholesterol. Science 294, 1354-1357

26R.E. Pagano (2003) Endocytic trafficking of glycosphingolipids in sphingolipid storage diseases. Philos Trans R Soc Lond B Biol Sci 358, 885-891

27X. Fu (2001) 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 276, 38378-38387

28B.A. Janowski (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728-731

29D.S. Ory (2000) Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta 1529, 331-339

30L. Liscum , R.M. Ruggiero and J.R. Faust (1989) The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J Cell Biol 108, 1625-1636

32K.M. Wojtanik and L. Liscum (2003) The transport of low density lipoprotein-derived cholesterol to the plasma membrane is defective in NPC1 cells. J Biol Chem 278, 14850-14856

33J.E. Vance (2006) Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett 580, 5518-5524

34G.H. Thomas (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

35M.E. Higgins (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

36E.B. Neufeld (1999) The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo. J Biol Chem 274, 9627-9635

37H. Watari (1999) Mutations in the leucine zipper motif and sterol-sensing domain inactivate the Niemann-Pick C1 glycoprotein. J Biol Chem 274, 21861-21866

38H. Runz (2008) NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat 29, 345-350

39K. Malathi (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, 547-556

40M. Sym , M. Basson and C. Johnson (2000) A model for niemann-pick type C disease in the nematode Caenorhabditis elegans. Curr Biol 10, 527-530

41X. Huang (2005) A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis. Development 132, 5115-5124

44M. Kuwamura (1993) Type C Niemann-Pick disease in a boxer dog. Acta Neuropathol 85, 345-348

45A.L. Mutka (2004) Secretion of sterols and the NPC2 protein from primary astrocytes. J Biol Chem 279, 48654-48662

46N. Friedland (2003) Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc Natl Acad Sci U S A 100, 2512-2517

47D.C. Ko (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, 2518-2525

48D.E. Sleat (2004) Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A 101, 5886-5891

49S.K. Loftus (1997) Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277, 232-235

51V.M. Rimkunas (2008) In vivo antisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick type C- associated liver disease. Hepatology 47, 1504-1512

52S.U. Walkley (1995) Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside immunoreactivity. Neuroscience 68, 1027-1035

53C. Xie (2000) Cholesterol is sequestered in the brains of mice with Niemann-Pick type C disease but turnover is increased. J Neuropathol Exp Neurol 59, 1106-1117

54M. Zervas , K. Dobrenis and S.U. Walkley (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

55S. Takikita (2004) Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J Neuropathol Exp Neurol 63, 660-673

56Y. Higashi (1993) Cerebellar degeneration in the Niemann-Pick type C mouse. Acta Neuropathol 85, 175-184

57W. Yu (2005) Neurodegeneration in heterozygous Niemann-Pick type C1 (NPC1) mouse: implication of heterozygous NPC1 mutations being a risk for tauopathy. J Biol Chem 280, 27296-27302

58M.C. Gondre-Lewis , R. McGlynn and S.U. Walkley (2003) Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Curr Biol 13, 1324-1329

59T. Cox (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355, 1481-1485

60M. Zervas (2001) Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol 11, 1283-1287

61M.C. Patterson (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6, 765-772

62S.H. Mellon (2007) Neurosteroid regulation of central nervous system development. Pharmacol Ther 116, 107-124

63L.D. Griffin (2004) Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat Med 10, 704-711

64S.J. Langmade (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, 13807-13812

65A. Frolov (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, 46414-46421

66J.J. Repa (2007) Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse. J Neurosci 27, 14470-14480

67D.C. Ko (2005) Cell-autonomous death of cerebellar purkinje neurons with autophagy in Niemann-Pick type C disease. PLoS Genet 1, 81-95

69D.J. Klionsky (2003) A unified nomenclature for yeast autophagy-related genes. Dev Cell 5, 539-545

70Z. Xie and D.J. Klionsky (2007) Autophagosome formation: core machinery and adaptations. Nat Cell Biol 9, 1102-1109

71Y. Ohsumi and N. Mizushima (2004) Two ubiquitin-like conjugation systems essential for autophagy. Semin Cell Dev Biol 15, 231-236

72Y. Kabeya (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 5720-5728

73I. Tanida , T. Ueno and E. Kominami (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, 47704-47710

74I. Tanida (2005) Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 1, 84-91

75D.J. Klionsky and S.D. Emr (2000) Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721

76T. Noda and Y. Ohsumi (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273, 3963-3966

77A. Yamamoto , M.L. Cremona and J.E. Rothman (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172, 719-731

78R.A. Nixon (2007) Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 120, 4081-4091

79T. Pan (2008) The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease. Brain, Jan 10 [Epub ahead of print]

80B. Ravikumar (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36, 585-595

81K. Kiselyov (2007) Autophagy, mitochondria and cell death in lysosomal storage diseases. Autophagy 3, 259-262

82A. Williams (2006) Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. Curr Top Dev Biol 76, 89-101

83A. Kuma (2004) The role of autophagy during the early neonatal starvation period. Nature 432, 1032-1036

84M. Komatsu (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884

85S. Shimizu (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 6, 1221-1228

86T. Shintani and D.J. Klionsky (2004) Autophagy in health and disease: a double-edged sword. Science 306, 990-995

87G. Liao (2007) Cholesterol accumulation is associated with lysosomal dysfunction and autophagic stress in Npc1−/−mouse brain. Am J Pathol 171, 962-975

88C.D. Pacheco , R. Kunkel and A.P. Lieberman (2007) Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 16, 1495-1503

89J. Cheng (2006) Cholesterol depletion induces autophagy. Biochem Biophys Res Commun 351, 246-252

90P. Lajoie (2005) The lipid composition of autophagic vacuoles regulates expression of multilamellar bodies. J Cell Sci 118, 1991-2003

91B. Levine and G. Kroemer (2008) Autophagy in the pathogenesis of disease. Cell 132, 27-42

93S. Vergarajauregui (2008) Autophagic dysfunction in mucolipidosis type IV patients. Hum Mol Genet, Jun 11 (Epub ahead of print]

94C. Settembre (2008) A block of autophagy in lysosomal storage disorders. Hum Mol Genet 17, 119-129

95Y. Cao (2006) Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem 281, 20483-20493

96M. Beck (2007) New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 121, 1-22

97Y.S. Hsu (1999) Niemann-Pick disease type C (a cellular cholesterol lipidosis) treated by bone marrow transplantation. Bone Marrow Transplant 24, 103-107

98M.L. Escolar (2005) Transplantation of umbilical-cord blood in babies with infantile Krabbe's disease. N Engl J Med 352, 2069-2081

99M.C. Patterson (1993) The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C. Neurology 43, 61-64

100M. Sylvain (1994) Magnetic resonance spectroscopy in Niemann-Pick disease type C: correlation with diagnosis and clinical response to cholestyramine and lovastatin. Pediatr Neurol 10, 228-232

101M. Jeyakumar (2001) Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation. Blood 97, 327-329

102A. Gaumann , H.J. Schlitt and E.K. Geissler (2008) Immunosuppression and tumor development in organ transplant recipients: the emerging dualistic role of rapamycin. Transpl Int 21, 207-217

N. Mizushima (2008) Autophagy fights disease through cellular self-digestion. Nature 451, 1069-1075

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *