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Nonselenium glutathione peroxidase in human brain - Elevated levels in Parkinson's disease and dementia with Lewy bodies

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AMERICAN JOURNAL OF PATHOLOGY 2002年第3期161卷 885-894页

作者： Power, JHT Shannon, JM Blumbergs, PC Gai, WP Flinders Univ S Australia Sch Med Dept Human Physiol Bedford Pk SA 5042 Australia Inst Med & Vet Sci Div Neuropathol Adelaide SA 5000 Australia Childrens Hosp Med Ctr Div Pulm Biol Cincinnati OH 45229 USA

Nonselenium glutathione peroxidase (NSGP) is a new member of the antioxidant family. Using antibodies to recombinant NSGP we have examined the distribution of this enzyme in normal, Parkinson's disease (PD), and dementia with Lewy body disease (DLB) brains. We have also co-localized this enzyme with a-synuclein as a marker for Lewy bodies. In normal brains there was a very low level of NSGP staining in astrocytes. In PD and DLB there were increases in the number and staining intensity of NSGP-positive astrocytes in both gray and white matter. Cell counting of NSGP cells in PD and DLB frontal and cingulated cortices indicated there was 10 to 15 times more positive cells in gray matter and three times more positive cells in white matter than in control cortices. Some neurons were positive for both a-synuclein and NSGP in PD and DLB, and double staining indicated that NSGP neurons contained either diffuse cytoplasmic a-synuclein deposits or Lewy bodies. In concentric Lewy bodies, a-synuclein staining was peripheral whereas NSGP staining was confined to the central core. Immunoprecipitation indicated there was direct interaction between a-synuclein and NSGP. These results suggest oxidative stress conditions exist in PD and DLB and that certain cells have responded by up-regulating this novel antioxidant enzyme.

关键词：抗体谷胱甘肽过氧化酶/代谢 Lewy体病/病理学神经组织蛋白质类/代谢帕金森病/病理学重组蛋白质类/代谢突触核蛋白类增量调节 α突触核蛋白人类

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RELP, a novel human REG-like protein with up-regulated expression in inflammatory and metaplastic gastrointestinal mucosa

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 11-20页

作者： Kämäräinen, M Heiskala, K Knuutila, S Heiskala, M Winqvist, O Andersson, LC Univ Helsinki Dept Pathol Haartman Inst FIN-00014 Helsinki Finland Univ Helsinki Cent Hosp Diagnost Lab Helsinki Finland Univ Helsinki Dept Med Genet Helsinki Finland RW Johnson Pharmaceut Res & Dev San Diego CA USA

2We screened expressed sequence tag databases for genes with up-regulated expression in inflammatory bowel diseases. A gene encoding a regenerating protein (REG)-like protein called RELP was identified and characterized. The relp gene encodes a major transcript of 1518 nucleotides, and two truncated splice variants. Unlike the reg genes, which form a cluster in chromosome 2, relp maps to chromosome 1p12-13.1. The predicted translation product is a 158-amino acid preprotein, showing 43% to 47% similarity to the REG proteins. It contains a 22-amino acid signal peptide, and a conserved calcium-dependent carbohydrate-recognition domain. Complementary DNA for the orthologous mouse gene was also cloned. The RELP protein is constitutively expressed in epithelial neuroendocrine cells of the small intestine and in parietal cells of the gastric mucosa. An up-regulated expression of RELP was seen in epithelial cells of inflammatory mucosa in ulcerative colitis and Crohn's disease, in regenerating epithelial borders of gastric ulcers, and in metaplastic epithelium in the antrum and the esophagus. Our findings suggest that RELP might be involved in inflammatory and metaplastic responses of the gastrointestinal epithelium.

关键词：碱基序列染色体人 1对数据库遗传学表达的序列标记胃黏膜/细胞学胃黏膜/病理学胃黏膜/生理学原位杂交荧光炎性肠疾病/遗传学炎性肠疾病/代谢肠黏膜/细胞学肠黏膜/病理学肠黏膜/生理学外源凝集素类 C型化生分子序列数据神经组织蛋白质类/遗传学神经组织蛋白质类/代谢蛋白质生物合成序列比对组织分布肿瘤细胞培养的增量调节/生理学动物人类小鼠

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Very large (CAG)_n DNA repeat expansions in the sperm of two spinocerebellar ataxia type 7 males

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HUMAN MOLECULAR GENETICS 1999年第13期8卷 2473-2478页

作者： Monckton, DG Cayuela, ML Gould, FK Brook, GJR de Silva, R Ashizawa, T Univ Glasgow Anderson Coll Inst Biomed & Life Sci Div Mol Genet Glasgow G11 6NU Lanark Scotland Baylor Coll Med Dept Neurol Houston TX 77030 USA Vet Affairs Med Ctr Houston TX 77030 USA

Genetic anticipation, i.e. increasing disease severity and decreasing age of onset from one generation to the next, is observed in a number of diseases, including myotonic dystrophy type 1, Huntington's disease and several of the spinocerebellar ataxias, All of these disorders are associated with the expansion of a trinucleotide repeat and array length is positively correlated with disease severity and inversely correlated with the age of onset, The expanded repeat is highly unstable and continues to expand from one generation to the next, providing a molecular explanation for anticipation. Spinocerebellar ataxia type 7 (SCA7) is one of the latest additions to the list of triplet repeat diseases and is distinct from the other SCAs in that it is accompanied by retinal degeneration, Pedigree analyses have previously revealed that the SCA7 repeat is highly unstable and liable to expand, in particular when transmitted by a male. Surprisingly, though, an under-representation of male transmission has also been reported. We now demonstrate directly by single molecule analyses that the expanded repeat is extraordinarily unstable in the male germline and biased toward massive increases. Nearly all of the mutant sperm of two SCA7 males contain alleles that are so large that most of the affected offspring would at best have a severe infantile form of the disease. Indeed, the gross under-representation of such very large expanded alleles in patients suggests that a significant proportion of such alleles might be associated with embryonic lethality or dysfunctional sperm.

关键词：等位基因早现遗传 DNA/分析神经组织蛋白质类/遗传学神经组织蛋白质类/代谢聚合酶链反应精子/代谢脊髓小脑共济失调/遗传学脊髓小脑共济失调/代谢三核苷酸重复扩增人类男(雄)性

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The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals

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MOLECULAR AND CELLULAR BIOLOGY 2000年第13期20卷 4736-4744页

作者： Su, YC Maurel-Zaffran, C Treisman, JE Skolnik, EY NYU Med Ctr Skirball Inst Biomol Med Dept Cell Biol New York NY 10016 USA NYU Med Ctr Skirball Inst Biomol Med Dept Pharmacol New York NY 10016 USA

We have previously shown that the Ste20 kinase encoded by misshapen (msn) functions upstream of the c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase module in Drosophila. msn is required to activate the Drosophila JNK, Basket (Bsk), to promote dorsal closure of the embryo. A mammalian homolog of Msn, Nck interacting kinase, interacts with the SH3 domains of the SH2-SH3 adapter protein Nck. We now show that Msn likewise interacts with Dreadlocks (Dock), the Drosophila homolog of Nck dock is required for the correct targeting of photoreceptor axons. We have performed a structure-function analysis of Msn in vivo in Drosophila in order to elucidate the mechanism whereby Msn regulates JNK and to determine whether msn, like dock, is required for the correct targeting of photoreceptor axons. We show that Msn requires both a functional kinase and a C-terminal regulatory domain to activate JNK in vivo in Drosophila. A mutation in a PXXP motif on Msn that prevents it from binding to the SH3 domains of Dock does not affect its ability to rescue the dorsal closure defect in msn embryos, suggesting that Dock is not an upstream regulator of msn in dorsal closure. Larvae with only this mutated form of Msn show a marked disruption in photoreceptor axon targeting, implicating an SH3 domain protein in this process;however, an activated form of Msn is not sufficient to rescue the dock mutant phenotype. Mosaic analysis reveals that msn expression is required in photoreceptors in order for their axons to project correctly. The data presented here genetically link msn to two distinct biological events, dorsal closure and photoreceptor axon pathfinding, and thus provide the first evidence that Ste20 kinases of the germinal center kinase family play a role in axonal pathfinding. The ability of Msn to interact with distinct classes of adapter molecules in dorsal closure and photoreceptor axon pathfinding may provide the flexibility that allows it to link to distinct upstream s

关键词：衔接蛋白质类信号转导氨基酸特征结构轴突/代谢果蝇属/胚胎学果蝇蛋白质类胚胎非哺乳动物眼/胚胎学眼/神经支配眼/代谢神经节无脊椎动物/胚胎学神经节无脊椎动物/代谢 JNK丝裂原活化蛋白激酶类丝裂原激活蛋白激酶类/遗传学丝裂原激活蛋白激酶类/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢脯氨酸蛋白质丝氨酸苏氨酸激酶/遗传学蛋白质丝氨酸苏氨酸激酶/代谢信号传导构效关系 p21活化激酶类 src同源域动物

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The fluorescent congo red derivative, (trans, trans) -: 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse β-pleated sheet structures in postmortem human neurodegenerative disease brains

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AMERICAN JOURNAL OF PATHOLOGY 2001年第3期159卷 937-943页

作者： Schmidt, ML Schuck, T Sheridan, S Kung, MP Kung, H Zhuang, ZP Bergeron, C Lamarche, JS Skovronsky, D Giasson, BI Lee, VMY Trojanowski, JQ Univ Penn Dept Pathol & Lab Med Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Radiol Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Pharmacol Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Toronto Toronto ON Canada Univ Sherbrooke Dept Pathol Sherbrooke PQ J1K 2R1 Canada

A novel Congo red-derived fluorescent probe (trans, trans), - 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) that binds to amyloid plaques of postmortem Alzheimer's disease brains and in transgenic mouse brains in vivo was designed as a prototype imaging agent for Alzheimer's disease. In the current study, we used BSB to probe postmortem tissues from patients with various neurodegenerative diseases with diagnostic lesions characterized by fibrillar intra- or extracellular lesions and compared these results with standard histochemical dyes such as thioflavin S and immunohistochemical stains specific for the same lesions. These data show that BSB binds not only to extracellular amyloid beta protein, but also many intracellular lesions composed of abnormal tau and synuclein proteins and suggests that radioiodinated BSB derivatives or related ligands may be useful imaging agents to monitor diverse amyloids in vivo.

关键词：淀粉样β肽类/代谢脑/代谢脑/病理学尸体荧光染料神经组织蛋白质类/代谢神经变性疾病/代谢神经变性疾病/病理学苯乙烯类突触核蛋白类 tau蛋白质类/代谢成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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CREB-binding protein sequestration by expanded polyglutamine

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HUMAN MOLECULAR GENETICS 2000年第14期9卷 2197-2202页

作者： McCampbell, A Taylor, JP Taye, AA Robitschek, J Li, M Walcott, J Merry, D Chai, YH Paulson, H Sobue, G Fischbeck, KH NINDS Neurogenet Branch NIH Bethesda MD 20892 USA Nagoya Univ Sch Med Dept Neurol Showa Ku Aichi Japan Thomas Jefferson Univ Philadelphia PA 19107 USA Univ Iowa Coll Med Dept Neurol Iowa City IA 52242 USA

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion results in an expanded polyglutamine tract, which likely confers a novel, toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamine expansion, In this report we present evidence that CREB-binding protein (CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3, We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA, Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture, These data support a CBP-sequestration model of polyglutamine expansion disease.

关键词： CREB结合蛋白质细胞死亡/药物作用细胞系细胞核/代谢细胞培养的 DNA结合蛋白质类真菌蛋白质类/代谢绿色荧光蛋白质类 HeLa细胞萤光素酶类/代谢发光蛋白质类/代谢 Machado-Joseph病/遗传学 Machado-Joseph病/代谢小鼠转基因肌萎缩脊髓性/遗传学肌萎缩脊髓性/代谢神经组织蛋白质类/代谢核蛋白质类/代谢肽类/代谢肽类/药理学 RNA 信使/代谢阻遏蛋白质类酿酒酵母蛋白质类阴囊/代谢四唑鎓盐类/药理学噻唑类/药理学时间因素反式激活因子类/代谢转录因子/代谢转录遗传三核苷酸重复扩增动物人类男(雄)性小鼠

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HuD RNA recognition motifs play distinct roles in the formation of a stable complex with AU-rich RNA

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MOLECULAR AND CELLULAR BIOLOGY 2000年第13期20卷 4765-4772页

作者： Park, SM Myszka, DG Yu, M Littler, SJ Laird-Offringa, IA Univ So Calif Norris Canc Ctr Keck Sch Med Los Angeles CA 90089 USA Univ Utah Sch Med Huntsman Canc Inst Salt Lake City UT 84132 USA

Human neuron-specific RNA-binding protein HuD belongs to the family of Hu proteins and consists of two N-terminal RNA recognition motifs (RRM1 and -2), a hinge region, and a C-terminal RRM (RRM3). Hu proteins can bind to AU-rich elements in the 3' untranslated regions of unstable mRNAs, causing the stabilization of certain transcripts. We have studied the interaction between HuD and prototype mRNA instability elements of the sequence UU(AUUU)(n)AUU using equilibrium methods and real-time kinetics (surface plasmon resonance using a BIACORE). We show that a single molecule of HuD requires at least three AUUU repeats to bind tightly to the RNA. Deletion of RRM1 reduced the K-d by 2 orders of magnitude and caused a decrease in the association rate and a strong increase in the dissociation rate of the RNA-protein complex, as expected when a critical RNA-binding domain is removed. In contrast, deletion of either RRM2 or -3, which only moderately reduced the affinity, caused marked increases in the association and dissociation rates. The slower binding and stabilization of the complex observed in the presence of all three RRMs suggest that a change in the tertiary structure occurs during binding. The individual RRMs bind poorly to the RNA (RRM1 binds with micromolar affinity, while the affinities of RRM2 and -3 are in the millimolar range). However, the combination of RRM1 and either RRM2 or RRM3 in the context of the protein allows binding with a nanomolar affinity. Thus, the three RRMs appear to cooperate not only to increase the affinity of the interaction but also to stabilize the formed complex. Kinetic effects, similar to those described here, could play a role in RNA binding by many multi-RRM proteins and may influence the competition between proteins for RNA-binding sites and the ability of RNA-bound proteins to be transported intracellularly.

关键词： 3'非翻译区结合部位基因 fos 突变神经组织蛋白质类/遗传学神经组织蛋白质类/代谢 RNA/化学 RNA/代谢 RNA稳定性 RNA结合蛋白质类/遗传学 RNA结合蛋白质类/代谢重复序列核酸表面等离激元人类

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Protein surveillance machinery in brains with spinocerebellar ataxia type 3:: Redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions

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ANNALS OF NEUROLOGY 2002年第3期51卷 302-310页

作者： Schmidt, T Lindenberg, KS Krebs, A Schöls, L Laccone, F Herms, J Rechsteiner, M Riess, O Landwehrmeyer, GB Univ Ulm Dept Neurol D-89075 Ulm Germany Univ Tubingen Dept Med Genet D-72074 Tubingen Germany Univ Freiburg Dept Neurol D-7800 Freiburg Germany Ruhr Univ Bochum Dept Neurol D-4630 Bochum Germany Univ Gottingen Inst Human Genet D-3400 Gottingen Germany Univ Gottingen Dept Pathol D-3400 Gottingen Germany Univ Utah Sch Med Dept Biochem Salt Lake City UT USA

Intracellular aggregates commonly forming neuronal intranuclear inclusions are neuropathological hallmarks of spinocerebellar ataxia type 3 and of other disorders characterized by expanded polyglutamine-(poly-Q) tracts. To characterize cellular responses to these aggregates, we performed an immunohistochemical analysis of neuronal intranuclear inclusions in pontine neurons of patients affected by spinocerebellar ataxia type 3, using a panel of antibodies directed against chaperones and proteasome subunits. A subset of the neuronal intranuclear inclusions stained positively for the chaperones Hsp90alpha and HDJ-2, a member of the Hsp40 family. Most neuronal intranuclear inclusions were ubiquitin positive, suggesting degradation by ubiquitin-dependent proteasome pathways. Surprisingly, only a fraction of neuronal intranuclear inclusions were immunopositive for antibodies directed against subunits of the 20S proteolytic core, whereas most inclusions were stained by antibodies directed against subunits of the 11S and 19S regulatory particles. These results suggest that the proteosomal proteolytic machinery that actively degrades neuronal intranuclear inclusions is assembled in only a fraction of pontine neurons in end stage spinocerebellar ataxia type 3. The dissociation between regulatory subunits and the proteolytic core and the changes in subcellular subunit distribution suggest perturbations of the proteosomal machinery in spinocerebellar ataxia type 3 brains.

关键词：腺苷三磷酸酶类/代谢细胞核/代谢半胱氨酸内肽酶类/代谢内肽酶类/代谢热休克蛋白质类/代谢免疫组织化学包涵体/代谢 Machado-Joseph病/代谢分子监控蛋白类/代谢多酶复合物/代谢神经组织蛋白质类/代谢神经元/代谢肽碎片/代谢肽水解酶类/代谢脑桥/代谢蛋白酶体内肽酶复合物组织分布人类

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Molecular cloning and functional characterization of a human homologue of centaurin-α

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期262卷 237-244页

作者： Venkateswarlu, K Cullen, PJ Univ Bristol Sch Med Sci Dept Biochem Bristol BS8 1TD Avon England

We report here the molecular cloning, expression, and characterisation of a human homologue of rat centaurin-alpha, which we have termed centaurin-alpha(1). The cDNA contains a single open reading frame, which encodes a 373-amino-acid protein with a calculated molecular weight of 43,429 Daltons. Centaurin-alpha(1) shows high identity at the amino acid level with the other centaurin-alpha homologues, p42(IP4) and PIP3BP. Northern analysis revealed that centaurin-alpha(1) expresses as a single 2.5-kb transcript, mainly in the brain. Recombinant centaurin-alpha(1) binds the inositol head group of PtdIns(3,4,5)P-3 and Ins(1,3,4,5)P-4, with high affinity (K-d 139.7 +/- 10.5 nM) and inositol phosphate specificity, consistent with it functioning as a putative PtdIns(3,4,5)P-3 receptor. In keeping with this conclusion, we have shown that GFP-tagged centaurin-alpha(1) recruits to the plasma membrane in a PI 3-kinase-dependent manner and the recruitment is inhibited by the PI 3-kinase inhibitor wortmannin, These results suggest that centaurin-alpha(1) can function as an in vivo PtdIns(3, 4, 5)P-3 receptor. (C) 1999 Academic Press.

关键词：衔接蛋白质类信号转导氨基酸序列雄二烯类/药理学碱基序列结合部位脑/代谢 CHO细胞载体蛋白质类/化学载体蛋白质类/遗传学载体蛋白质类/代谢细胞膜/药物作用细胞膜/代谢克隆分子仓鼠亚科肌醇磷酸类/代谢分子序列数据神经组织蛋白质类/化学神经组织蛋白质类/遗传学神经组织蛋白质类/代谢器官特异性磷脂酰肌醇磷酸盐类/代谢 RNA 信使/分析 RNA 信使/遗传学重组融合蛋白质类/代谢序列同源性氨基酸锌指动物人类

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RNAs that interact with the Fragile X syndrome RNA binding protein FMRP

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第3期275卷 973-980页

作者： Sung, YJ Conti, J Currie, JR Brown, WT Denman, RB New York State Inst Basic Res Dev Disabil Dept Mol Biol Staten Isl NY 10314 USA New York State Inst Basic Res Dev Disabil Dept Human Genet Staten Isl NY 10314 USA

The Fragile X protein FMRP is an RNA binding protein whose targets are not well known;yet, these RNAs may play an integral role in the disease's etiology, Using a biotinylated-FMRP affinity resin, we isolated RNAs from the parietal cortex of a normal adult that bound FMRP, These RNAs were amplified by differential display (DDRT-PCR) and cloned and their identities determined. Nine candidate RNAs were isolated;five RNAs, including FMR1 mRNA, encoded known proteins. Four others were novel. The specificity of binding was demonstrated for each candidate RNA. The domains required for binding a subset of the RNAs were delineated using FMRP truncation mutant proteins and it was shown that only the KH2 domain was required for binding. Binding occurred independently of homoribopolymer binding to the C-terminal arginine-glycine-rich region (RGG box), suggesting that FMRP may bind multiple RNAs simultaneously. (C) 2000 Academic Press.

关键词：碱基序列结合竞争性生物素化作用脑/代谢色谱法亲和克隆分子脆性X智力低下蛋白质脆性X综合征/遗传学脆性X综合征/代谢分子序列数据突变神经组织蛋白质类/遗传学神经组织蛋白质类/代谢蛋白质结合 RNA 信使/分析 RNA 信使/遗传学 RNA 信使/分离和提纯 RNA 信使/代谢 RNA结合蛋白质类/遗传学 RNA结合蛋白质类/代谢动物人类小鼠

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