Understanding Niemann-Pick type C disease: A fat problem

Current Opinion in Neurology

Volumn 16, Issue 2, 2003, Pages 155-161

  Vincent, Inez ^a,c   Bu, Bitao ^c   Erickson, Robert P ^b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

^c Box 357705 ^*

Author keywords

Cdk5; Cholesterol; Lipid trafficking; Neurodegeneration; Neurofibrillary tangle; Phosphorylated neurofilament; Phosphorylated tau

Indexed keywords

CYCLIN DEPENDENT KINASE 5; CYCLIN DEPENDENT KINASE 5 INHIBITOR; CYCLIN DEPENDENT KINASE INHIBITOR; UNCLASSIFIED DRUG;

CENTRAL NERVOUS SYSTEM DISEASE; DETERIORATION; DISEASE COURSE; FIBROBLAST; FUTUROLOGY; GENETIC DISORDER; HOMEOSTASIS; HUMAN; LIPID METABOLISM; LIPID STORAGE; MEDICAL RESEARCH; MEMBRANE VESICLE; NERVE DEGENERATION; NEUROLOGIC DISEASE; NEUROPATHOLOGY; NIEMANN PICK DISEASE; NPC1 GENE; PREMATURITY; REVIEW; STATISTICAL SIGNIFICANCE;

ANIMALS; BRAIN; CENTRAL NERVOUS SYSTEM DISEASES; CHOLESTEROL; GLYCOSPHINGOLIPIDS; HUMANS; LIPID METABOLISM, INBORN ERRORS; MICE; MICE, TRANSGENIC; NEURODEGENERATIVE DISEASES; NIEMANN-PICK DISEASES;

EID: 0037396865     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019052-200304000-00006     Document Type: Review

References (49)

1. Garver WS, Heidenreich RA. The Niemann-Pick C proteins and trafficking of cholesterol through the late endosomal/lysosomal system. Curr Mol Med 2002; 2:485-505. This is an excellent review integrating current knowledge on the function of NPC1 and NPC2 with that on intracellular cholesterol trafficking.
2. Strauss JF, Liu P, Christenson LK, Watari H. Sterols and intracellular vesicular trafficking: lessons from the study of NPC1. Steroids 2002; 67:947-951. This is a concise up-to-date description of the biological function and interactions of NPC1 and NPC2.
3. Prinz W. Cholesterol trafficking in the secretory and endocytic systems. Semin Cell Dev Biol 2002; 13:197-203.
4. Ribeiro I, Marcao A, Amaral O, et al. Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations. Hum Genet 2001; 109:24-32. The authors performed mutational analysis of 13 patients (12 Portuguese) and found 10 novel mutations.
5. Bauer P, Knoblich R, Bauer C, et al. NPC1: complete genomic sequence, mutation analysis, and characterization of haplotypes. Hum Mutat 2002; 19:30-38. The authors established the complete genomic sequence, mutations, and haplotypes of the NPC-1 gene, identifying nine novel mutations. One synonymous and three non-synonymous exonic, 11 intronic, and one promoter single nucleotide polymorphism were newly identified. The presence of a common missense mutation (2572G-2793T) in 41% of controls suggested that haplotypic background influences the expression of NPC1.
6. Tarugi P, Ballarini G, Bembi B, et al. Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts. J Lipid Res 2002; 43:1908-1919. The authors reported unexpected discrepancies between complementary DNA and genomic DNA sequences, including expression of a single mutant allele (monoallelic expression) in patients having compound heterozygosity, and mutant messenger RNA with a different mutation in the corresponding genomic DNA. They proposed a fascinating idea that coexistence of bi-allelic and mono-allelic expression in different tissues could play a role in differential clinical expression, or contribute to phenotypic variability. This is worth pursuing especially in brain versus other tissues.
7. Kaminski WE, Klunemann HH, Ibach B, et al. Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease. J Inherit Metab Dis 2002; 25:385-389.
8. Millat G, Chikh K, Naureckiene S, et al. Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. Am J Hum Genet 2001; 69:1013-1021. This was a mutational study of nearly all the known NPC2 cases which provided the start of phenotype/genotype correlations.
9. Klunemann HH, Elleder M, Kaminski WE, et al. Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Ann Neurol 2002; 52:743-749. This was the first study to describe adult-onset NPC caused by NPC2 mutations, with lysosomal storage restricted to neurons and no obvious storage in visceral organs.
10. Imrie J, Wraith JE. Isolated splenomegaly as the presenting feature of Niemann-Pick disease type C. Arch Dis Child 2001; 84:427-429. This is a thoughtful case report of probable NPC1 patients who presented with splenomegaly and in whom neurological symptoms did not occur for 3-6 years.
11. Elleder M, Houstkova H, Zeman J, et al. Pulmonary storage with emphysema as a sign of Niemann-Pick type C2 disease (second complementation group): report of a case. Virchows Arch 2001; 439:206-211. This is a single case report with extensive post-mortem findings.
12. Sun X, Marks DL, Park WD, et al. Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1. Am J Hum Genet 2001; 68:1361-1372.
13. Vanier MT. Prenatal diagnosis of Niemann-Pick diseases types A, B and C. Prenat Diagn 2002; 22:630-632.
14. Amigo L, Mendoza H, Castro J, et al. Relevance of Niemann-Pick type C1 protein expression in controlling plasma cholesterol and billiary lipid secretion in mice. Hepatology 2002; 36:819-828. This was an important in-vivo study that implicated NPC1 in mobilization of cholesterol for biliary excretion when there is excess dietary cholesterol. Elevated intermediate-density lipoprotein and total serum cholesterol were found on regular and high cholesterol diets.
15. Alpy F, Wendling C, Rio MC, Tomasetto C. MENTHO, a MLN64 homologue devoid of the START domain. J Biol Chem 2002; 277:50780-50787. This is a study of an interesting late endosomal membrane protein which demonstrates that its overexpression does not correct the NPC cellular phenotype but leads to the accumulation of enlarged endosomes.
16. Blom TS, Koivusalo M, Kuismanen E, et al. Mass spectrometric analysis reveals as increase in plasma membrane polyunsaturated phospholipid species upon cellular cholesterol loading. Biochemistry 2001; 40:14635-14644. This paper uses the clever approach of comparing lipid composition of viruses which bud from rafts with non-rafts in NPC cells to show that cholesterol and polyunsaturated phospholipid content increases in both kinds of plasma membrane.
17. Feng B, Tabas I. ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages: mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity. J Biol Chem 2002; 277:43271-43280. This is a study of consequences of free cholesterol loading on ABCA1 levels which further elucidates the role of NPC1.
18. Oram JF. The cholesterol mobilizing transporter ABCA1 as a new therapeutic target for cardiovascular disease. Trends Cardiovasc Med 2002; 12:170-175.
19. Garrigues A, Escargueil AE, Orlowski S. The multidrug transporter, P-glycoprotein, actively mediates cholesterol redistribution in the cell membrane. Proc Natl Acad Sci U S A 2002; 99:10347-10352. This is an important study implicating the 'flippase' activity of multidrug-resistant P-glycoproteins in stabilizing rafts and caveolae.
20. Voikar V, Rauvala H, Ikonen E. Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease. Behav Brain Res 2002; 132(1):1-10. This study has established methods for assessing motor and cognitive impairment and the temporal appearance of NPC symptoms in npc1 -/- mice. The findings may be useful for evaluating potential treatment strategies.
21. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol 2001; 12:105-112. This is a useful up-to-date account of cholesterol metabolism in the brain.
22. Frolov A, Srivastava K, Daphna-Iken D, et al. Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. J Biol Chem 2001, 276:46414-46421. A mutation resulting in a threefold increase in the low-density lipoprotein receptor in Chinese hamster ovary cells led to cholesterol accumulation in an 'NPC-like' compartment but cholesterol delivery to the endoplasmic reticulum and plasma membrane was normal.
23. Lebrand C, Corti M, Goodson H, et al. Late endosome motility depends on lipids via the small GTPase Rab7. Embo J 2002, 21:1289-1300. Late endosomes loaded with cholesterol lost their motility in a Rab7-dependent manner. Cholesterol accumulation increased the amount of membrane-associated Rab7 suggesting that cholesterol helps regulate the Rab7 cycle while Rab7 helps control late endocytic vesicle movements.
24. Choudhury A, Dominguez M, Puri V, et al. Rab proteins mediate Golgi transport of caveola-internalized glycosphingolipids and correct lipid trafficking in Niemann-Pick C cells. J Clin Invest 2002; 109:1541-1550. Using fluorescently labeled analogues these authors corrected the deficient Golgi-targeted uptake of lactosyl-ceramide and cholera toxin seen in NPC1 cells by overexpression of Rab7 or Rab9. Cholesterol storage as assayed with filipin was greatly decreased: an expected result as normal cells overloaded with cholesterol show the same defect as NPC1 cells.
25. Lange Y, Ye J, Rigney M, Steck TL. Dynamics of lysosomal cholesterol in Niemann-Pick type C and normal human fibroblasts. J Lipid Res 2002; 43:198-204. This is an important study showing that the markedly increased endolysomal cholesterol in NPC1 cells circulates to the cell surface at the normal rate.
26. Garver WS, Krishnan K, Gallagos JR, et al. Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae. J Lipid Res 2002; 43:579-589. This describes a technical tour-de-force in which caveolae were purified from NPC1 genotypically diverse fibroblasts with NPC1+/- and NPC1 -/- found to be deficient in cholesterol despite increased amounts of caveolin 1 and 2 in these caveolae.
27. Karten B, Vance DE, Campenot RB, Vance JE. Trafficking of cholesterol from cell bodies to distal axons in Niemann-Pick C1-deficient neurons. J Biol Chem 2002; 27:27. This is an elegant cell biological study of cholesterol transport in sympathetic neurons from npc1 -/- mice, and the first to describe cholesterol changes within individual neurons. Additional studies of this nature are bound to reveal important aspects of NPC1 and NPC2 function in neuronal cells.
28. Mauch DH, Nagler K, Schumacher S, et al. CNS synaptogenesis promoted by glia-derived cholesterol. Science 2001; 294:1354-1357. This exciting paper fractionated glia-conditioned media to discover that cholesterol-containing apo E substituted for glia in neuronal/astrocyte co-cultures.
29. -/- mice showing that degeneration of nerve fibers followed by cell bodies can be found as early as day 9 postnatally.
30. Meiner V, Shpitzen S, Mandel H, et al. Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C. Genet Med 2001; 3:343-348. The authors performed mutational analysis of nine Israeli patients finding eight novel mutations. Using an in-vitro cholesterol-loading protocol for patients' fibroblasts, they found an inverse correlation between clinical severity and cholesterol ester levels.
31. Bu B, Klunemann H, Suzuki K, et al. Niemann-Pick disease type C yields possible clue for why cerebellar neurons do not form neurofibrillary tangles. Neurobiol Dis 2002; 11:285-297.
32. Erickson RP, Garver WS, Camargo F, et al. Pharmacological and genetic modifications of somatic cholesterol do not substantially after the course of CNS disease in Niemann-Pick C mice. J Inher Metab Dis 2000; 23:54-62.
33. Camargo F, Erickson RP, Garver WS, et al. Cyclodextrins in the treatment of a mouse model of Niemann-Pick C disease. Life Sci 2001; 70:131-142. These authors found that two out of three different preparations of 2-hydroxypropyl cyclodextrins delayed neurological symptoms in npc1 -/- mice.
34. German DO, Quintero EM, Liang C, et al. Degeneration of neurons and glia in the Niemann-Pick C mouse is unrelated to the low-density lipoprotein receptor. Neuroscience 2001; 105:999-1005. Stereological counting methods were used to quantify glial cells and Purkinje cell number in npc1 -/- mice at a number of time points. The co-presence of nullizygosity for the LDL receptor did not change the rate of loss of these cells.
35. Taniguchi M, Shinoda Y, Ninomiya H, et al. Sites and temporal changes of gangliosides GM1/GM2 storage in the Niemann-Pick disease type C mouse brain. Brain Dev 2001; 23:414-421. This immunohistochemical study of GM1 and GM2 in npc1 -/- brain found different sites of storage for the two gangliosides: GM1 in neurons and astrocytes and GM2 in neurons and macrophages.
36. Liu Y, Wu YP, Wada R, et al. Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann-Pick C disease mouse. Hum Mol Genet 2000; 9:1087-1092. Using the b1-4Gal Nac transferase knockout, these authors presented GM2 and GA1 and 2 accumulation in the npc1 -1- brain. Despite a dramatic improvement in neuropathological appearance, neurodegeneration proceeded at the usual rate.
37. Zervas M, Somers KL, Thrall MA, Walkley SU. Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol 2001; 11:1283-1287. This is an important paper reinforcing the relevance of glycosphingolipids in CNS pathology in NPC.
38. German DC, Liang CL, Song T, et al. Neurodegeneration in the Niemann-Pick C mouse: glial involvement. Neuroscience 2002; 109:437-450. This was a standard neuropathological study of the Npc1 -/- mice focusing on changes in astrocytes and microglia which swell in size and increase their content of inclusion bodies as the neurodegeneration proceeds.
39. Zervas M, Dobrenis K, Walkley SU. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 2001; 60:49-64.
40. Sawamura N, Gong JS, Garver WS, et al. Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice. J Biol Chem 2001; 276:10314-10319.
41. Husseman JW, Nochlin D, Vincent I. Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol Aging 2000; 21:815-828.
42. Bu B, Li J, Davies P, Vincent I. Deregulation of cdk5, hyperphosphorylation, and cytoskeletal pathology in the Niemann-Pick type C murine model. J Neurosci 2002; 22:6515-6525. This elegant immunohistochemical and quantitative immunoblot analysis of npc1 -/- brains disclosed increased cleavage of p35 to p25 with increased activity of cdk5 and hyperphosphorylation of medium-weight neurofilaments, tan and MAP2. Despite these changes, neurofibrillary tangles are not seen in mouse Npc1 -/- brains although they are in humans.
43. Smith DS, Tsai LH. Cdk5 behind the wheel: a role in trafficking and transport? Trends Cell Biol 2002; 12:28-36. This is a comprehensive review of the relationship between Cdk5 and cytoskeletal, membrane, and adhesion systems.
44. Erickson RP, Bernard O. Studies on neuronal death in the mouse model of Niemann-Pick C disease. J Neurosci Res 2002; 68:738-744. Overexpression of human bcl2 in transgenic npc1 -/- mice did not alter the course of neurodegeneration.
45. Loftus SK, Erickson RP, Walkley SU, et al. Rescue of neurodegeneration in Niemann-Pick C mice by a prion-promoter-driven Npc1 cDNA transgene. Hum Mol Genet 2002; 11:3107-3114. This pivotal study demonstrated that expression of wild-type NPC1 predominantly in the CNS of npc1 -/- mice prevented neurodegeneration while visceral storage continued.
46. 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; 52:351-355. The question of interacting genes in the progression of NPC was raised by Tarugi, et al [6]. This paper shows that ApoE4 is an important genetic risk factor in NPC1.
47. 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; 276:4454-4460. Amyloid β-protein accumulation as aggregates in the locations and cells in which cholesterol accumulates in NPC suggesting a direct interaction between aggregated amyloid β-protein and cholesterol.
48. Burns M, Duff K. Cholesterol in Alzheimer's disease and tauopathy. Ann N Y Acad Sci 2002; 977:367-375.
49. Liscum L, Arnio E, Anthony M, et al. Identification of a pharmaceutical compound that partially corrects the Niemann-Pick C phenotype in cultured cells. J Lipid Res 2002; 43:1708-1717. This paper characterizes the action of a potential therapeutic drug for NPC is characterized. It was found by screening a library of 44,200 compounds!