A Riddle Wrapped in a Mystery: Understanding Niemann-Pick Disease, Type C

Patterson, Marc C.

doi:10.1097/01.nrl.0000094627.78754.5b

Cited by 81 publications

(60 citation statements)

References 102 publications

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“…phenotype that in man is indistinguishable from lack of NPC1 function (6). Furthermore, the NPC2 hypomorphic mouse closely resembles the NPC1 null mouse both with respect to disease progression and with biochemical and cellular neuropathological criteria (8).…”

Section: Fig 5 Secretion Of De Novo Sterols Is Not Dependent On Npcmentioning

confidence: 74%

“…[4][5][6][7][8][9][10][11][12][13][14] C]Cholesterol (specific activity 58 mCi/mmol), [1␣,2␣(n)- 3 H]cholesterol (specific activity 41.0 Ci/mmol), [ 3 H]acetic acid (specific activity 5.10 -9.00 Ci/mmol), Hybond-C membrane, and the ECL reagents were purchased from Amersham Biosciences. The polyclonal anti-glial fibrillary acidic protein antibody was from Dako, and anti-lysobisphosphatidic acid antibody (13) was a gift from Jean Gruenberg (University of Geneva).…”

Section: Methodsmentioning

confidence: 99%

“…The disease is caused by mutations in either the NPC1 or NPC2 gene (6). The NPC1 protein is a late endosomal membrane protein harboring a sterol-sensing domain, whereas NPC2 is a secretory protein that has cholesterol binding properties and uses the mannose 6-phosphate marker for late endosomal targeting (7).…”

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confidence: 99%

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Secretion of Sterols and the NPC2 Protein from Primary Astrocytes

Mutka

Lusa

Linder

et al. 2004

Journal of Biological Chemistry

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Astrocytes secrete cholesterol in lipoprotein particles.Here we show that primary murine embryonic astrocytes secrete endogenously synthesized cholesterol but also the cholesterol precursors desmosterol and lathosterol. In astrocyte membranes, desmosterol and cholesterol were the predominant sterols. Astrocytes derived from Niemann-Pick type C lipidosis (NPC1 ؊/؊ ) mice displayed late endosomal cholesterol deposits, but the secretion of biosynthetic sterols from the cells was not inhibited. Both wild-type and NPC1 ؊/؊ astrocytes secreted the NPC2 protein. Size-exclusion chromatography combined with electron microscopy showed that the majority of sterols were secreted separately from NPC2 in heterogeneous spherical particles with an average diameter of 20 nm. These data suggest that NPC2 and the majority of sterols secreted from astrocytes are not released together and that the secretion of neither sterols nor NPC2 requires NPC1 function. In addition, the findings reveal a complexity of sterol species in astrocytes and bring up the possibility that some of the effects assigned to astrocyte cholesterol may be attributed to its penultimate precursors. The brain is the most cholesterol-rich organ in the body, containing roughly 25% of the unesterified cholesterol present in the whole individual. The input of cholesterol into the brain comes entirely, or almost entirely, from in situ synthesis because blood lipoproteins do not cross the blood-brain-barrier (1). Glial cells are thought to be responsible for a large part of this biosynthetic activity. Most of the sterol in the brain is acquired during myelination in the early stages of development and is produced by oligodendrocytes (2).Astrocytes, the most abundant glial cells, are intimately associated with neuronal synapses and secrete cholesterol in lipoprotein particles. Astrocytes have been proposed to provide cholesterol for synapse formation (3) as well as to participate in the recycling of cholesterol after injury (4). Nascent lipoproteins isolated from neonatal mouse astrocytes are a heterogeneous population of particles in the size range of plasma high density lipoproteins and appear to be composed of two separate classes that contain either apolipoprotein E or J (5).Niemann-Pick type C disease (NPC) 1 is an inherited, fatal neurodegenerative disorder in which large amounts of cholesterol and sphingolipids accumulate intracellularly within late endocytic organelles. The disease is caused by mutations in either the NPC1 or NPC2 gene (6). The NPC1 protein is a late endosomal membrane protein harboring a sterol-sensing domain, whereas NPC2 is a secretory protein that has cholesterol binding properties and uses the mannose 6-phosphate marker for late endosomal targeting (7). The exact functions of the proteins remain unknown, but genetic evidence suggests that they function in concert to facilitate lysosomal lipid egress (8).In the NPC1 Ϫ/Ϫ mouse astrocytes are considered to contribute to neurodegeneration (9, 10). Interestingly, NPC1 Ϫ/Ϫ astrocytes were shown t...

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Section: Fig 5 Secretion Of De Novo Sterols Is Not Dependent On Npcmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

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Secretion of Sterols and the NPC2 Protein from Primary Astrocytes

Mutka

Lusa

Linder

et al. 2004

Journal of Biological Chemistry

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“…Defects in cholesterol homeostasis and metabolism have been linked directly or indirectly to many disease conditions. Niemann-Pick type C (NPC) disease is one such cholesterol homeostasis-related disorder characterized by aberrant accumulation of free cholesterol in late endosome and lysosome-like compartments (Patterson, 2003). Normal cells take up exogenous cholesterol through the receptor-mediated low density lipoprotein (LDL) endocytic pathway.…”

Section: Introductionmentioning

confidence: 99%

Drosophila Niemann-Pick Type C-2genes control sterol homeostasis and steroid biosynthesis: a model of human neurodegenerative disease

et al. 2007

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Mutations in either of the two human Niemann-Pick type C (NPC) genes, NPC1 and NPC2, cause a fatal neurodegenerative disease associated with abnormal cholesterol accumulation in cells. npc1a, the Drosophila NPC1 ortholog, regulates sterol homeostasis and is essential for molting hormone (20-hydroxyecdysone; 20E) biosynthesis. While only one npc2 gene is present in yeast, worm, mouse and human genomes, a family of eight npc2 genes (npc2a-h) exists in Drosophila. Among the encoded proteins, Npc2a has the broadest expression pattern and is most similar in sequence to vertebrate Npc2. Mutation of npc2a results in abnormal sterol distribution in many cells, as in Drosophila npc1a or mammalian NPC mutant cells. In contrast to the ecdysteroid-deficient, larvallethal phenotype of npc1a mutants, npc2a mutants are viable and fertile with relatively normal ecdysteroid level. Mutants in npc2b, another npc2 gene, are also viable and fertile, with no significant sterol distribution abnormality. However, npc2a; npc2b double mutants are not viable but can be rescued by feeding the mutants with 20E or cholesterol, the basic precursor of 20E. We conclude that npc2a functions redundantly with npc2b in regulating sterol homeostasis and ecdysteroid biosynthesis, probably by controlling the availability of sterol substrate. Moreover, npc2a; npc2b double mutants undergo apoptotic neurodegeneration, thus constituting a new fly model of human neurodegenerative disease.

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“…Niemann-Pick type C (NPC) disease is one of the genetic disorders characterized by a failure to release unesterified cholesterol from lysosomes or late endosomes. NPC cells acquire apolipoprotein B/E (apoB/E)-containing lipoprotein particles through receptor-mediated endocytosis (10,11), thereby accumulating cholesterol within acidic compartments. Lipids like sterol, sphingomyelin, and glycolipids accumulate in cells throughout the body and cause hepatosplenomegaly and progressive central nervous system degeneration (12).…”

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confidence: 99%