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Parkinson's disease is not associated with combined α-synuclein/apolipoprotein E susceptibility genotype

ANNALS OF NEUROLOGY 2001年第5期49卷 665-668页

作者： Khan, N Graham, E Dixon, P Morris, C Mander, A Clayton, D Vaughan, J Quinn, N Lees, A Daniel, S Wood, N de Silva, R Newcastle Gen Hosp MRC Neurochem Pathol Unit Newcastle Upon Tyne NE4 6BE Tyne & Wear England UCL Royal Free & Univ Coll Sch Med Weston Inst Neurol Studies London England Inst Neurol Parkinson Dis Soc Brain Res Ctr London England Univ London Neurogenet Sect Neurol Inst Dept Clin Neurol London WC1N 3BG England

A recent study showed significant association of sporadic Parkinson's disease with a polymorphism within the alpha -synuclein gene and closely linked DNA markers on chromosome 4q and the APOE epsilon4 allele. A combined alpha -synuclein/APOE-epsilon4 genotype increased the relative risk of developing Parkinson's disease 12-fold. We failed to confirm this association in a much larger sample of histopathologically proven cases of Parkinson's disease and controls.

关键词：等位基因载脂蛋白E类/遗传学染色体人 4对/遗传学遗传标记/遗传学基因型神经组织蛋白质类/遗传学帕金森病/遗传学多态现象遗传/遗传学突触核蛋白类 α突触核蛋白女(雌)性人类男(雄)性中年人

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Neuropilin-2 regulates the development of select cranial and sensory nerves and hippocampal mossy fiber projections

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NEURON 2000年第1期25卷 43-56页

作者： Chen, H Bagri, A Zupicich, JA Zou, YM Stoeckli, E Pleasure, SJ Lowenstein, DH Skarnes, WC Chédotal, A Tessier-Lavigne, M Univ Calif San Francisco Dept Anat San Francisco CA 94243 USA Univ Calif San Francisco Dept Biochem & Biophys Howard Hughes Med Inst San Francisco CA 94243 USA Univ Calif San Francisco Dept Neurol San Francisco CA 94243 USA Hop La Pitie Salpetriere INSERM U106 F-75013 Paris France Univ Basel Dept Integrat Biol CH-4051 Basel Switzerland Univ Calif Berkeley Dept Mol & Cell Biol Berkeley CA 94720 USA

Neuropilin-1 and neuropilin-2 bind differentially to different class 3 semaphorins and are thought to provide the ligand-binding moieties in receptor complexes mediating repulsive responses to these semaphorins. Here, we have studied the function of neuropilin-2 through analysis of a neuropilin-2 mutant mouse, which is viable and fertile. Repulsive responses of sympathetic and hippocampal neurons to Sema3F but not to Sema3A are abolished in the mutant. Marked defects are observed in the development of several cranial nerves, in the initial central projections of spinal sensory axons, and in the anterior commissure, habenulo-interpeduncular tract, and the projections of hippocampal mossy fiber axons in the infrapyramidal bundle. Our results show that neuropilin-2 is an essential component of the Sema3F receptor and identify key roles for neuropilin-2 in axon guidance in the PNS and CNS.

关键词：轴突/生理学 COS细胞颅神经/化学颅神经/胚胎学颅神经/病理学基因表达调控发育期/生理学基因报告糖蛋白类/生理学缰/化学缰/胚胎学缰/病理学小鼠基因敲除苔藓纤维海马/化学苔藓纤维海马/胚胎学苔藓纤维海马/病理学诱变/生理学神经组织蛋白质类/遗传学神经组织蛋白质类/代谢神经元传入/化学神经元传入/生理学神经元传入/超微结构神经纤毛蛋白质1 周围神经/化学周围神经/细胞学周围神经/胚胎学信号素3A 脊神经根/化学脊神经根/细胞学脊神经根/胚胎学颈上神经节/化学颈上神经节/胚胎学颈上神经节/病理学 β半乳糖苷酶类/遗传学动物小鼠

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α-synuclein and Parkinson's disease:: Selective neurodegenerative effect of α-synuclein fragment on dopaminergic neurons in vitro and in vivo

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ANNALS OF NEUROLOGY 2000年第5期47卷 632-640页

作者： Forloni, G Bertani, I Calella, AM Thaler, F Invernizzi, R Ist Ric Farmacol Mario Negri Dept Neurosci I-20157 Milan Italy Ist Ric Farmacol Mario Negri Dept Mol Biochem & Pharmacol I-20157 Milan Italy

Missense mutations in the alpha-synuclein gene were associated with a familial Parkinson's disease, and alpha-synuclein is a major component of Lewy bodies, the intracellular inclusions that neuropathologically characterize Parkinson's disease. We investigated the neurotoxic activity of the nonamyloid component (NAC) of senile plaque, the fibrillogenic fragment (61-95) of alpha-synuclein, in vitro and in vivo. Rat primary mesencephalic neurons were exposed for 6 days to low concentrations of preaggregated NAC (0.5-10.0 mu M). The number of dopaminergic neurons and dopamine content were both reduced with no effect on the general viability of the cells. At higher concentrations (25-100 mu M), the neurotoxic effect of NAC was extended to all neurons. Preaggregated NAC was also toxic on a PC12 dopaminergic cell line differentiated with nerve growth factor. The intracellular localization of NAC has been identified by the exposure of neuronal cells to fluorescent peptide In vivo application of aggregated NAC in the substantia nigra induced loss of dopaminergic neurons. Our data illustrate the selective neurotoxic effect of NAC for dopaminergic neurons and support the central role of alpha-synuclein in the pathogenesis of Parkinson's disease.

关键词：载体蛋白质类/遗传学细胞集合细胞培养的疾病模型动物多巴胺/遗传学多巴胺/代谢突变误义/遗传学神经变性/遗传学神经生长因子/代谢神经组织蛋白质类/遗传学神经元/代谢帕金森病/遗传学帕金森病/病理学肽碎片/遗传学肽类/遗传学肽类/代谢点突变/遗传学黑质/代谢黑质/病理学 α突触核蛋白动物男(雄)性大鼠

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Search for the PARK3 founder haplotype in a large cohort of patients with Parkinson's disease from Northern Germany

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ANNALS OF HUMAN GENETICS 1999年第4期63卷 285-291页

作者： Klein, C Vieregge, P Hagenah, J Sieberer, M Doyle, E Jacobs, H Gasser, T Breakefield, XO Risch, NJ Ozelius, LJ Massachusetts Gen Hosp Mol Neurogenet Unit Boston MA 02114 USA Harvard Univ Sch Med Dept Neurol Boston MA 02114 USA Harvard Univ Sch Med Dept Genet Boston MA 02114 USA Harvard Univ Sch Med Program Neurosci Boston MA 02114 USA Univ Lubeck Dept Neurol D-23538 Lubeck Germany Univ Munich Klinikum Grosshadern Dept Neurol Munich Germany Stanford Univ Dept Genet Stanford CA 94305 USA

A founder haplotype on chromosome 2p for autosomal dominant Parkinson's disease (PD) has been postulated for two families of Northern European descent, and a new mutation in the alpha-synuclein gene (Ala30Pro) has been found in a German PD family. We evaluated 85 German PD patients and 85 ethnically matched controls for shared markers on chromosome 2p and for the new a-synuclein mutation. We found no evidence for linkage disequilibrium suggesting that the putative founder mutation on chromosome 2p is not a common cause of PD in the local population. Furthermore, no patient carried the Ala30Pro change, supporting earlier findings that mutations in the a-synuclein gene are extremely rare.

关键词：等位基因病例对照研究染色体人 2对/遗传学队列研究建立者效应基因频率基因显性德国单元型连锁不平衡神经组织蛋白质类/遗传学帕金森病/遗传学点突变突触核蛋白类 α突触核蛋白老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Functional domains within the degenerin/epithelial sodium channel (Deg/ENaC) superfamily of ion channels

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JOURNAL OF PHYSIOLOGY-LONDON 1999年第3期520卷 631-644页

作者： Benos, DJ Stanton, BA Univ Alabama Birmingham Dept Physiol & Biophys Birmingham AL 35294 USA Dartmouth Med Sch Dept Physiol Hanover NH 03755 USA

Application of recombinant DNA technology and electrophysiology to the study of amiloride-sensitive Naf channels has resulted in an enormous increase in the understanding of the structure-function relationships of these channels. Moreover, this knowledge has permitted the elucidation of the physiological roles of these ion channels in cellular processes as diverse as transepithelial salt and water movement, taste perception, volume regulation, nociception, neuronal function, mechanosensation, and even defaecation. Although members of this ever-growing superfamily of ion channels (the Deg/ENaC superfamily) share little amino acid identity, they are all organized similarly, namely, two short N- and C-termini, two short membrane-spanning segments, and a very large extracellular loop domain. In this brief Topical Review, we discuss the structural features of each domain of this Deg/ENaC superfamily and, using ENaC as a model, show how each domain relates to overall channel function.

关键词：氨基酸序列/遗传学细胞质/代谢离子通道/遗传学离子通道/生理学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/生理学钠通道/遗传学钠通道/生理学动物

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The genetics of Parkinson's disease

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CURRENT OPINION IN GENETICS & DEVELOPMENT 2000年第3期10卷 292-298页

作者： de Silva, HA Khan, NL Wood, NW UCL Royal Free & Univ Coll Sch Med Reta Lila Weston Inst Neurol Studies London W1P 6DB England Univ London Inst Neurol Dept Clin Neurol London WC1N 3BG England

The effort to map the entire human genome has led recently to the important milestone publication in late 1999 of the complete sequence of chromosome 22. This has been facilitated by increasingly sophisticated tools for genetic analysis and the ensuing wealth of detailed genetic information. The quest for genetic factors contributing to Parkinson's disease and parkinsonian disorders has revealed a progressively complex picture implicating gene mutations in the rarer, autosomally inherited forms of Parkinson's disease and the interplay of genetic and/or environmental factors in the common sporadic forms of the disorder. These findings not only reiterate the complex genetic heterogeneity of Parkinson's disease but could also point towards common pathogenic mechanisms in Parkinson's disease and related neurodegenerative disorders.

关键词：染色体图染色体人 22对连接酶类突变神经组织蛋白质类/遗传学帕金森病/遗传学蛋白质类/遗传学突触核蛋白类硫酯水解酶类/遗传学泛素硫酯酶泛素蛋白连接酶类动物人类

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Enhanced association of mutant triosephosphate isomerase to red cell membranes and to brain microtubules

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第3期97卷 1026-1031页

作者： Orosz, F Wágner, G Liliom, K Kovács, J Baróti, K Horány, M Farkas, T Hollán, S Ovádi, J Hungarian Acad Sci Biol Res Ctr Inst Enzymol H-1518 Budapest Hungary Eotvos Lorand Univ Fac Sci Dept Gen Zool H-1445 Budapest Hungary Natl Inst Haematol & Immunol H-1113 Budapest Hungary Hungarian Acad Sci Inst Biochem Biol Res Ctr H-6701 Szeged Hungary

In a Hungarian family with triosephosphate isomerase (TPI;D-glyceraldehyde-3-phosphate keto-isomerase, EC 5.3.1.1) deficiency, two germ-line identical, but phenotypically differing compound heterozygote brothers tone of them with neurological disorder) have been identified with the same very low (< 5%) TPI activity and 20- or 40-fold higher erythrocyte dihydroxyacetone phosphate levels as compared with normal controls. Our present studies with purified TPI and hemolysates revealed the binding of TPI, and the binding of human wild-type and mutant TPIs in hemolysate, to the red cell membrane, and the interference of binding with other hemolysate proteins. The binding of the mutant TPI is enhanced as compared with the wild-type enzyme. The increased binding is influenced by both the altered structure of the mutant and the changes in the red cell membrane. Compared with binding of glyceraldehyde-3-phosphate dehydrogenase, the isomerase binding is much less sensitive to ionic strength or blocking of the N-terminal tail of the band-3 transmembrane protein. The binding of TPIs to the membrane decreases the isomerase activity, resulting in extremely high dihydroxyacetone phosphate levels in deficient cells. In cell-free brain extract, tubulin copolymerizes with TPI and with other cytosolic proteins forming highly decorated microtubules as shown by immunoblot analysis with anti-TPI antibody and by electron microscopic images. The efficacy order of TPI binding to microtubules is propositus > brother without neurological disorder > normal control. This distinct microcompartmentation of mutant proteins may be relevant in the development of the neurodegenerative process in TPI deficiency and in other, more common neurological diseases.

关键词：贫血溶血性先天性/酶学贫血溶血性先天性/遗传学基底神经节疾病/酶学基底神经节疾病/遗传学结合竞争性生物转运脑/酶学细胞膜/代谢密码子/遗传学二羟丙酮磷酸/代谢红细胞/酶学杂合子大分子物质微管/酶学神经组织蛋白质类/缺乏神经组织蛋白质类/遗传学神经组织蛋白质类/代谢点突变蛋白质结合终止区遗传丙糖磷酸异构酶/缺乏丙糖磷酸异构酶/遗传学丙糖磷酸异构酶/代谢微管蛋白/代谢动物牛人类男(雄)性大鼠

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The structure of the ligand-binding domain of neurexin Iβ:: Regulation of LNS domain function by alternative splicing

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CELL 1999年第1期99卷 93-101页

作者： Rudenko, G Nguyen, T Chelliah, Y Südhof, TC Deisenhofer, J Univ Texas SW Med Ctr Howard Hughes Med Inst Dallas TX 75235 USA Univ Texas SW Med Ctr Dept Biochem Dallas TX 75235 USA Univ Texas SW Med Ctr Ctr Basic Neurosci Dallas TX 75235 USA Univ Texas SW Med Ctr Dept Mol Genet Dallas TX 75235 USA

Neurexins are expressed in hundreds of isoforms on the neuronal cell surface, where they may function as cell recognition molecules. Neurexins contain LNS domains, folding units found in many proteins like the G domain of laminin A, agrin, and slit. The crystal structure of neurexin I beta, a single LNS domain, reveals two seven-stranded beta sheets forming a jelly roll fold with unexpected structural similarity Po lectins. The LNS domains of neurexin and agrin undergo alternative splicing that modulates their affinity for protein ligands in a neuron-specific manner. These splice sites are localized within loops at one edge of the jelly roll, suggesting a distinct protein interaction surface in LNS domains that is regulated by alternative splicing.

关键词：聚集蛋白/化学聚集蛋白/遗传学选择性剪接保守序列结晶学 X线基因表达外源凝集素类/化学外源凝集素类/遗传学配体分子序列数据神经组织蛋白质类/化学神经组织蛋白质类/遗传学神经元/化学蛋白质折叠蛋白质结构二级蛋白质结构三级序列同源性氨基酸

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OTX2 directly interacts with LIM1 and HNF-3β

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第1期267卷 64-70页

作者： Nakano, T Murata, T Matsuo, I Aizawa, S Kumamoto Univ Sch Med Inst Mol Embryol & Genet Dept Morphogenesis Kumamoto 8600811 Japan

Otx2 is a paired-class homeobox gene, and its functions in anterior visceral endoderm and/or anterior mesendoderm have been suggested to be vital for head development in mammals. Several transcription factors are expressed in these tissues, and mutant mice analyses have suggested the interactions of the Otx2 gene cascade with the Lim1 or HNF-3 beta cascade. Here we show that OTX2 directly associates with LIM1 and HNF-S beta;OTX2 binds to the LIM1 homeodomain (HD) with its C-terminal region, whereas both HD and C-terminal regions of OTX2 bind to the HNF-S beta fork head domain or OTX2 HD, The luciferase assay with the P3C sequence, a specific DNA binding sequence for paired-class homeobox genes, has demonstrated that LIM1 enhances, but HNF-3 beta represses, OTX2-directed gene expression. Direct interactions of OTX2 with LIM1 or HNF-S beta may play important roles in anterior visceral endoderm and/or anterior mesendoderm to constitute transcriptional regulatory networks for head development. (C) 2000 Academic Press.

关键词： DNA结合蛋白质类/遗传学 DNA结合蛋白质类/代谢基因同源盒谷胱甘肽转移酶/遗传学 HeLa细胞肝细胞核因子3β 同源盒结构域蛋白质类/遗传学同源盒结构域蛋白质类/代谢动力学萤光素酶类/遗传学神经组织蛋白质类/遗传学神经组织蛋白质类/代谢核蛋白质类/遗传学核蛋白质类/代谢 Otx转录因子类重组融合蛋白质类/生物合成重组蛋白质类/代谢反式激活因子类/遗传学反式激活因子类/代谢转录因子/代谢转录遗传转染动物人类小鼠

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Modulation of CRX transactivation activity by phosducin isoforms

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MOLECULAR AND CELLULAR BIOLOGY 2000年第14期20卷 5216-5226页

作者： Zhu, XM Craft, CM Univ So Calif Keck Sch Med Dept Cell & Neurobiol Doheny Eye Inst Los Angeles CA 90089 USA Univ So Calif Mary D Allen Lab Vis Res Doheny Eye Inst Los Angeles CA 90089 USA

Phosducin (Phd) and Phd-like proteins (PhLPs) selectively bind guanine nucleotide protein (G protein) beta gamma subunits (G beta gamma), while Phd-like orphan proteins (PhLOPs) lack the major functional domain for the binding of G beta gamma. A retina- and pineal gland-specific transcription factor, cone-rod homeobox (CRX), was identified by a yeast two-hybrid screen using PhLOP1 as the bait. Direct protein-protein interactions between Phd or PhLOP1 and CRX were demonstrated using a beta-galactosidase quantitative assay in the yeast two-hybrid system and were confirmed by an in vitro binding assay and a glutathione S-transferase (GST) pull-down assay. To determine if the interaction with Phd or PhLOP1 affected CRX transactivation, a 120-bp interphotoreceptor retinoid binding protein (IRBP) promoter-luciferase reporter construct containing a CRX consensus element (GATTAA) was cotransfected into either COS-7 or retinoblastoma Weri-Rb-1 cells with expression constructs for CRX and either Phd or PhLOP1, Phd and PhLOP1 inhibited the transcriptional activation activity of CRX by 50% during transient cotransfection in COS-7 cells and by 70% in Weri-Rb-1 cells and COS-7 cells stably transfected with CRX. Phd inhibited CRX transactivation in a dose-dependent manner. Whereas Phd is a cytoplasmic phosphoprotein, coexpression of Phd with CRX results in Phd being localized both in the cytoplasm and nucleus. By contrast, PhLOP1 is found in the nucleus even without CRX coexpression. To address the physiological relevance of these potential protein interacting partners, we identified immunoreactive proteins for Phd and CRX in retinal cytosolic and nuclear fractions. Immunohistochemical analysis of bovine retinas reveals colocalization of Phd isoforms with CRX predominantly in the inner segment of cone cells, with additional costaining in the outer nuclear layer and the synaptic region. Our findings demonstrate that both Phd and PhLOP1 interact directly with CRX and that each dimin

关键词： COS细胞细胞核/代谢眼蛋白质类/遗传学眼蛋白质类/代谢 GTP结合蛋白质调节剂基因表达谱谷胱甘肽转移酶/遗传学谷胱甘肽转移酶/代谢同源盒结构域蛋白质类/遗传学同源盒结构域蛋白质类/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢 Otx转录因子类磷蛋白类/遗传学磷蛋白类/代谢光感受器细胞脊椎动物/代谢蛋白质亚型/遗传学蛋白质亚型/代谢重组蛋白质类/遗传学重组蛋白质类/代谢视网膜/生理学视黄醇结合蛋白质类/遗传学视黄醇结合蛋白质类/代谢反式激活因子类/遗传学反式激活因子类/代谢转录激活肿瘤细胞培养的双杂交系统技术酵母菌/遗传学动物牛小鼠

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