Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann- Pick type C disease.

Abstract:

:Niemann-Pick type C disease (NP-C) is an inherited neurovisceral lipid storage disorder characterized by progressive neurodegeneration. Most cases of NP-C result from inactivating mutations of NPC1, a recently identified member of a family of genes encoding membrane-bound proteins containing putative sterol sensing domains. By using a specific antipeptide antibody to human NPC1, we have here investigated the cellular and subcellular localization and regulation of NPC1. By light and electron microscopic immunocytochemistry of monkey brain, NPC1 was expressed predominantly in perisynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphological characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NP-C mouse, a spontaneous mutant model of human NP-C, by amino-cupric-silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurological phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kDa protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH4Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NP-C. Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggest that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NP-C.

authors

Patel SC,Suresh S,Kumar U,Hu CY,Cooney A,Blanchette-Mackie EJ,Neufeld EB,Patel RC,Brady RO,Patel YC,Pentchev PG,Ong WY

doi

10.1073/pnas.96.4.1657

subject

Has Abstract

pub_date

1999-02-16 00:00:00

pages

1657-62

issue

4

eissn

0027-8424

issn

1091-6490

journal_volume

96

pub_type

杂志文章
  • Pupil dilation reflects perceptual selection and predicts subsequent stability in perceptual rivalry.

    abstract::During sustained viewing of an ambiguous stimulus, an individual's perceptual experience will generally switch between the different possible alternatives rather than stay fixed on one interpretation (perceptual rivalry). Here, we measured pupil diameter while subjects viewed different ambiguous visual and auditory st...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0707727105

    authors: Einhäuser W,Stout J,Koch C,Carter O

    更新日期:2008-02-05 00:00:00

  • Adult mouse brain gene expression patterns bear an embryologic imprint.

    abstract::The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural ti...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0503357102

    authors: Zapala MA,Hovatta I,Ellison JA,Wodicka L,Del Rio JA,Tennant R,Tynan W,Broide RS,Helton R,Stoveken BS,Winrow C,Lockhart DJ,Reilly JF,Young WG,Bloom FE,Lockhart DJ,Barlow C

    更新日期:2005-07-19 00:00:00

  • The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning.

    abstract::The oxazolidinones represent the first new class of antibiotics to enter into clinical usage within the past 30 years, but their binding site and mechanism of action has not been fully characterized. We have determined the crystal structure of the oxazolidinone linezolid bound to the Deinococcus radiodurans 50S riboso...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0804276105

    authors: Wilson DN,Schluenzen F,Harms JM,Starosta AL,Connell SR,Fucini P

    更新日期:2008-09-09 00:00:00

  • Tertiary structure of myohemerythrin at low resolution.

    abstract::X-ray diffraction studies have produced a low resolution image and also located the iron atoms of a monomeric hemerythrin from muscles of a sipunculan worm. These results reveal the course of the polypeptide chain and some details of the active center. ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.72.6.2160

    authors: Hendrickson WA,Klippenstein GL,Ward KB

    更新日期:1975-06-01 00:00:00

  • Abnormal development and dye coupling produced by antisense RNA to gap junction protein in mouse preimplantation embryos.

    abstract::Antisense RNA to the 27/32-kDa rat liver gap junction (GJ) protein was used to explore the role of GJs in preimplantation embryos. When all blastomeres of two- and four-cell embryos were injected with GJ antisense RNA, the percentage of embryos compacted at 60 hr of development was reduced to less than 20%, while 90% ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.14.5444

    authors: Bevilacqua A,Loch-Caruso R,Erickson RP

    更新日期:1989-07-01 00:00:00

  • Prostaglandin F2 alpha stimulates phosphatidylinositol 4,5-bisphosphate hydrolysis and mobilizes intracellular Ca2+ in bovine luteal cells.

    abstract::The present studies were conducted to determine whether prostaglandin F2 alpha (PGF2 alpha) stimulates the production of "second messengers" derived from inositol phospholipid hydrolysis and increases intracellular free Ca2+ ([Ca2+]i) in isolated bovine luteal cells. PGF2 alpha provoked rapid (10 sec) and sustained (u...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.11.3728

    authors: Davis JS,Weakland LL,Weiland DA,Farese RV,West LA

    更新日期:1987-06-01 00:00:00

  • A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells.

    abstract::We characterize a sonic hedgehog (Shh) signaling domain restricted to the adventitial layer of artery wall that supports resident Sca1-positive vascular progenitor cells (AdvSca1). Using patched-1 (Ptc1(lacZ)) and patched-2 (Ptc2(lacZ)) reporter mice, adventitial Shh signaling activity was first detected at embryonic ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0711382105

    authors: Passman JN,Dong XR,Wu SP,Maguire CT,Hogan KA,Bautch VL,Majesky MW

    更新日期:2008-07-08 00:00:00

  • Genetic regulation of octane dissimilation plasmid in Pseudomonas.

    abstract::The enzymes responsible for the oxidation of n-octane to octanoic acid or beyond in Pseudomonas oleovorans are octane inducible and are coded by genes borne on a transmissible extrachromosomal element. The octane to octanoate enzymes induced by octane are repressed by octanol. The chromosome also carries genes coding ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.4.1137

    authors: Chakrabarty AM,Chou G,Gunsalus IC

    更新日期:1973-04-01 00:00:00

  • Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates.

    abstract::The stress inoculation hypothesis presupposes that brief intermittent stress exposure early in life induces the development of subsequent stress resistance in human and nonhuman primates. Rodent studies, however, suggest a role for maternal care rather than stress exposure per se (i.e., the maternal mediation hypothes...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0506571103

    authors: Parker KJ,Buckmaster CL,Sundlass K,Schatzberg AF,Lyons DM

    更新日期:2006-02-21 00:00:00

  • Locations of adenovirus genes required for the replication of adenovirus-associated virus.

    abstract::We have used DNA transfection to identify several regions of the adenovirus genome needed to induce replication of the defective parvovirus, adenovirus-associated virus (AAV). Previous studies have indicated that only early adenovirus functions are needed to aid the replication of AAV. In this report, we demonstrate t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.3.1925

    authors: Janik JE,Huston MM,Rose JA

    更新日期:1981-03-01 00:00:00

  • Kinetics of sickle cell biorheology and implications for painful vasoocclusive crisis.

    abstract::We developed a microfluidics-based model to quantify cell-level processes modulating the pathophysiology of sickle cell disease (SCD). This in vitro model enabled quantitative investigations of the kinetics of cell sickling, unsickling, and cell rheology. We created short-term and long-term hypoxic conditions to simul...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1424111112

    authors: Du E,Diez-Silva M,Kato GJ,Dao M,Suresh S

    更新日期:2015-02-03 00:00:00

  • Mei4p coordinates the onset of meiosis I by regulating cdc25+ in fission yeast.

    abstract::The kinase Cdc2p is a central regulator of entry into and progression through nuclear division during mitosis and meiosis in eukaryotes. Cdc2p is activated at the onset of mitosis by dephosphorylation on tyrosine-15, the phosphorylation status of which is determined mainly by the kinase Wee1p and the phosphatase Cdc25...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0702906104

    authors: Murakami-Tonami Y,Yamada-Namikawa C,Tochigi A,Hasegawa N,Kojima H,Kunimatsu M,Nakanishi M,Murakami H

    更新日期:2007-09-11 00:00:00

  • Location of the 18/28S ribosomal RNA genes in two Hawaiian Drosophila species by monoclonal immunological identification of RNA.DNA hybrids in situ.

    abstract::Using both heterologous rabbit antisera and mouse monoclonal antibody to RNA.DNA hybrids, we have mapped the in situ hybridization locus of the 18/28S ribosomal RNA fraction to a single large band on polytene autosome 3 in Drosophila heteroneura and Drosophila silvestris. This portion of the chromosome is not physical...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.78.6.3751

    authors: Stuart WD,Bishop JG,Carson HL,Frank MB

    更新日期:1981-06-01 00:00:00

  • A mutant murine leukemia virus with a single missense codon in pol is defective in a function affecting integration.

    abstract::We have used site-directed mutagenesis of cloned Moloney murine leukemia virus (MuLV) DNA to define a function encoded in the 3' region of the viral pol gene and required for efficient integration of viral DNA. One mutant, MuLV-SF1, contained a single base substitution (C to T at base 4950) that resulted in an arginin...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.20.6461

    authors: Donehower LA,Varmus HE

    更新日期:1984-10-01 00:00:00

  • A physiological role for oxalic acid biosynthesis in the wood-rotting basidiomycete Fomitopsis palustris.

    abstract::A metabolic mechanism for oxalic acid biosynthesis in the wood-rotting basidiomycete Fomitopsis palustris has been proposed on the basis of biochemical analyses of glucose metabolism. There was a strong correlation between glucose consumption and oxalate production. Oxalic acid was found to accumulate in the culture f...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.191389598

    authors: Munir E,Yoon JJ,Tokimatsu T,Hattori T,Shimada M

    更新日期:2001-09-25 00:00:00

  • Molecular cloning and expression of an additional epidermal growth factor receptor-related gene.

    abstract::Epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), and amphiregulin are structurally and functionally related growth regulatory proteins. These secreted polypeptides all bind to the 170-kDa cell-surface EGF receptor, activating its intrinsic kinase activity. However, amphiregulin exhibits dif...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.13.4905

    authors: Plowman GD,Whitney GS,Neubauer MG,Green JM,McDonald VL,Todaro GJ,Shoyab M

    更新日期:1990-07-01 00:00:00

  • Effects of binocular deprivation on the development of clustered horizontal connections in cat striate cortex.

    abstract::Intrinsic horizontal axon collaterals in the striate cortex of adult cats specifically link columns having the same preferred orientation; consequently, retrograde tracer injections result in intrinsic labeling that is sharply clustered. We have previously shown that the normal development of this circuitry involves t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.3.745

    authors: Callaway EM,Katz LC

    更新日期:1991-02-01 00:00:00

  • On the spin trapping and ESR detection of oxygen-derived radicals generated inside cells.

    abstract::Recently several attempts to identify oxygen-derived radicals in whole cells by spin trapping and electron spin resonance have been reported by using 5,5-dimethyl-1-pyrroline-N-oxide as the spin trap. In the present study, the feasibility of this method is examined. Chinese hamster V79 cells and human erythrocytes ser...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.83.20.7593

    authors: Samuni A,Carmichael AJ,Russo A,Mitchell JB,Riesz P

    更新日期:1986-10-01 00:00:00

  • Nonspecific binding to structured RNA and preferential unwinding of an exposed helix by the CYT-19 protein, a DEAD-box RNA chaperone.

    abstract::We explore the interactions of CYT-19, a DExD/H-box protein that functions in folding of group I RNAs, with a well characterized misfolded species of the Tetrahymena ribozyme. Consistent with its function, CYT-19 accelerates refolding of the misfolded RNA to its native state. Unexpectedly, CYT-19 performs another reac...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0603127103

    authors: Tijerina P,Bhaskaran H,Russell R

    更新日期:2006-11-07 00:00:00

  • Expression and nuclear envelope localization of biologically active fusion glycoprotein gB of herpes simplex virus in mammalian cells using cloned DNA.

    abstract::Herpes simplex virus (HSV) is known to bud from the inner membrane of the nuclear envelope. The structural gene for the glycoprotein gB, which is essential for virus entry and cell fusion induced by HSV type 1, has been cloned in a transient expression vector containing the adenovirus major late promoter, tripartite l...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.16.5675

    authors: Ali MA,Butcher M,Ghosh HP

    更新日期:1987-08-01 00:00:00

  • East African cheetahs: evidence for two population bottlenecks?

    abstract::A combined population genetic and reproductive analysis was undertaken to compare free-ranging cheetahs from east Africa (Acinonyx jubatus raineyi) with the genetically impoverished and reproductively impaired south African subspecies (Acinonyx jubatus jubatus). Like that of their south African counterparts, the quali...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.2.508

    authors: O'Brien SJ,Wildt DE,Bush M,Caro TM,FitzGibbon C,Aggundey I,Leakey RE

    更新日期:1987-01-01 00:00:00

  • Alpine ice evidence of a three-fold increase in atmospheric iodine deposition since 1950 in Europe due to increasing oceanic emissions.

    abstract::Iodine is an important nutrient and a significant sink of tropospheric ozone, a climate-forcing gas and air pollutant. Ozone interacts with seawater iodide, leading to volatile inorganic iodine release that likely represents the largest source of atmospheric iodine. Increasing ozone concentrations since the preindustr...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1809867115

    authors: Legrand M,McConnell JR,Preunkert S,Arienzo M,Chellman N,Gleason K,Sherwen T,Evans MJ,Carpenter LJ

    更新日期:2018-11-27 00:00:00

  • Three-dimensional structure of NADPH-cytochrome P450 reductase: prototype for FMN- and FAD-containing enzymes.

    abstract::Microsomal NADPH-cytochrome P450 reductase (CPR) is one of only two mammalian enzymes known to contain both FAD and FMN, the other being nitric-oxide synthase. CPR is a membrane-bound protein and catalyzes electron transfer from NADPH to all known microsomal cytochromes P450. The structure of rat liver CPR, expressed ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.16.8411

    authors: Wang M,Roberts DL,Paschke R,Shea TM,Masters BS,Kim JJ

    更新日期:1997-08-05 00:00:00

  • MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein.

    abstract::The MLL (mixed-lineage leukemia) gene is involved in many chromosomal translocations associated with acute myeloid and lymphoid leukemia. We previously identified a transcriptional repression domain in MLL, which contains a region with homology to DNA methyltransferase. In chromosomal translocations, the MLL repressio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1436338100

    authors: Xia ZB,Anderson M,Diaz MO,Zeleznik-Le NJ

    更新日期:2003-07-08 00:00:00

  • Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage.

    abstract::Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0510815103

    authors: Lee CH,Kang K,Mehl IR,Nofsinger R,Alaynick WA,Chong LW,Rosenfeld JM,Evans RM

    更新日期:2006-02-14 00:00:00

  • Transcriptomic network analyses shed light on the regulation of cuticle development in maize leaves.

    abstract::Plant cuticles are composed of wax and cutin and evolved in the land plants as a hydrophobic boundary that reduces water loss from the plant epidermis. The expanding maize adult leaf displays a dynamic, proximodistal gradient of cuticle development, from the leaf base to the tip. Laser microdissection RNA Sequencing (...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2004945117

    authors: Qiao P,Bourgault R,Mohammadi M,Matschi S,Philippe G,Smith LG,Gore MA,Molina I,Scanlon MJ

    更新日期:2020-06-02 00:00:00

  • Real-time attack on single Escherichia coli cells by the human antimicrobial peptide LL-37.

    abstract::Natural antimicrobial peptides (AMPs) provide prototypes for the design of unconventional antimicrobial agents. Existing bulk assays measure AMP activity but do not provide details of the growth-halting mechanism. We use fluorescence microscopy to directly observe the attack of the human antimicrobial peptide LL-37 on...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1101130108

    authors: Sochacki KA,Barns KJ,Bucki R,Weisshaar JC

    更新日期:2011-04-19 00:00:00

  • Modulation of muscle gene expression in Caenorhabditis elegans: differential levels of transcripts, mRNAs, and polypeptides for thick filament proteins during nematode development.

    abstract::The body-wall muscle cells of the nematode Caenorhabditis elegans produce thick filaments during embryonic, larval, and adult stages. These thick filaments contain two myosin isoforms, A and B, which assemble into different zones along the 10-microns lengths. Paramyosin, a protein homologous to myosin rods, forms a su...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.87.3.876

    authors: Honda S,Epstein HF

    更新日期:1990-02-01 00:00:00

  • IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection.

    abstract::Mounting effective T cell responses is critical for eliciting long-lasting immunity following viral infection and vaccination. A multitude of inhibitory and stimulatory factors are induced following infection, and it is the compilation of these signals that quantitatively and qualitatively program the ensuing effector...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0914500107

    authors: Brooks DG,Walsh KB,Elsaesser H,Oldstone MB

    更新日期:2010-02-16 00:00:00

  • Encroaching forests decouple alpine butterfly population dynamics.

    abstract::Over the past 50 years, the rising tree line along Jumpingpound Ridge in the Rocky Mountains of Alberta, Canada, has reduced the area of alpine meadows and isolated populations that reside within them. By analyzing an 11-year data set of butterfly population sizes for 17 subpopulations along the ridge, we show that fo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0705511104

    authors: Roland J,Matter SF

    更新日期:2007-08-21 00:00:00