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Ubiquitination of α-synuclein is not required for formation of pathological inclusions in α-synucleinopathies

AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 91-100页

作者： Sampathu, DM Giasson, BI Pawlyk, AC Trojanowski, JQ Lee, VMY Univ Penn Sch Med Ctr Neurodegenerat Dis Res Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Sch Med Inst Aging Philadelphia PA 19104 USA

alpha-Synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are neurodegenerative disorders in which abnormal inclusions containing alpha-synuclein accumulate in selectively vulnerable neurons and glia. In this report, immunohistochemistry demonstrates ubiquitin in subsets of alpha-synuclein inclusions in dementia with Lewy bodies and multiple system atrophy. Biochemistry demonstrates that alpha-synuclein in the sodium dodecyl sulfate-soluble fractions of diseased brains is ubiquitinated, with mono- and di-ubiquitinated species predominating over polyubiquitinated forms. Similar immunohistochemical and biochemical characteristics were observed in an A53T mutant human alpha-synuclein transgenic mouse model of neurodegenerative alpha-synucleinopathics. Furthermore, in vitro ubiquitination of alpha-synuclein fibrils recapitulated the pattern of alpha-synuclein ubiquitination observed in human disease and the A53T alpha-synuclein mouse model. These results suggest that ubiquitination of alpha-synuclein is not required for inclusion formation and follows the fibrillization of alpha-synuclein.

关键词：细胞分级分离疾病模型动物扣带回/细胞学扣带回/代谢扣带回/病理学包涵体/化学包涵体/代谢 Lewy体病/代谢 Lewy体病/病理学小鼠转基因多系统萎缩/代谢多系统萎缩/病理学神经组织蛋白质类/遗传学神经组织蛋白质类/代谢脊髓/细胞学脊髓/代谢突触核蛋白类泛素/代谢 α突触核蛋白成年人老年人老年人 80以上动物女(雌)性人类男(雄)性小鼠中年人

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Detection of the survival motor neuron (SMN) genes by FISH:: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients

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HUMAN MOLECULAR GENETICS 1999年第13期8卷 2525-2532页

作者： Vitali, T Sossi, V Tiziano, F Zappata, S Giuli, A Paravatou-Petsotas, M Neri, G Brahe, C Catholic Univ Rome Inst Med Genet I-00168 Rome Italy

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder which presents with various clinical phenotypes ranging from severe to very mild. All forms are caused by the homozygous absence of the survival motor neuron (SMN1) gene. SMN1 and a nearly identical copy (SMN2) are located in a duplicated region at 5q13 and encode identical proteins. The genetic basis for the clinical variability of SMA remains unclear, but it has been suggested that the copy number of SMN2 could influence the disease severity. We have assessed the number of SMN2 genes in patients with different clinical phenotypes by fluorescence in situ hybridization (FISH) using as SMN probe a mixture of small specific DNA fragments. Gene copy number was established by FISH on interphase nuclei, but the presence of two SMN2 genes on the same chromosome could also be revealed by FISH on metaphase spreads. All patients had at least two SMN2 genes. We found two or three copies of SMN2 in severely affected type I patients, three copies in intermediately affected type II patients, generally four copies in mildly affected type III patients and four or eight copies in patients with very mild adult-onset SMA, No alterations of the genes were detected by Southern blot and sequence analysis, suggesting that all gene copies of SMN2 were intact. These data provide additional evidence that the SMN2 genes modulate the disease severity and suggest that knowledge of the gene copy number could be of some prognostic value.

关键词：等位基因印迹法 DNA 细胞核/遗传学染色体人/遗传学 cAMP反应元件结合蛋白质 DNA探针原位杂交荧光分裂间期/遗传学中期/遗传学肌萎缩脊髓性/遗传学神经组织蛋白质类/遗传学聚合酶链反应多态性限制性片段长度多态现象单链构象 RNA结合蛋白质类人类

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Mouse numb is an essential gene involved in cortical neurogenesis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第12期97卷 6844-6849页

作者： Zhong, WM Jiang, MM Schonemann, MD Meneses, JJ Pedersen, RA Jan, LY Jan, YN Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94143 USA Univ Calif San Francisco Dept Physiol & Biochem San Francisco CA 94143 USA Univ Calif San Francisco Dept Obstet Gynecol & Reprod Sci San Francisco CA 94143 USA Yale Univ Dept Mol Cellular & Dev Biol New Haven CT 06511 USA

During neurogenesis of the mammalian neocortex, neural progenitor cells divide to generate daughter cells that either become neurons or remain as progenitor cells. The mouse numb (m-numb) gene encodes a membrane-associated protein that is asymmetrically localized to the apical cell membrane of dividing cortical progenitor cells and may be segregated to only the apical daughter cell that has been suggested to remain as a progenitor cell. To examine m-numb function during neural development, we generated a loss-of-function mutant allele of m-numb. Mice homozygous for this mutation exhibit severe defects in cranial neural tube closure and precocious neuron production in the forebrain and die around embryonic day 11.5 (E11.5). These findings suggest that m-numb is an essential gene that plays a role in promoting progenitor cell fate during cortical neurogenesis.

关键词：大脑皮质/胚胎学胚胎丢失膜蛋白质类/遗传学突变神经组织蛋白质类/遗传学神经管缺损/病因学神经元/生理学动物女(雌)性小鼠妊娠

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The GDNF family ligands and receptors - implications for neural development

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CURRENT OPINION IN NEUROBIOLOGY 2000年第1期10卷 103-110页

作者： Baloh, RH Enomoto, H Johnson, EM Milbrandt, J Washington Univ Sch Med Dept Pathol St Louis MO 63110 USA Washington Univ Sch Med Dept Internal Med St Louis MO 63110 USA Washington Univ Sch Med Dept Neurol St Louis MO 63110 USA Washington Univ Sch Med Dept Mol Biol & Pharmacol St Louis MO 63110 USA

The glial cell line derived neurotrophic factor (GDNF) family has recently been expanded to include four members, and the interactions between these neurotrophic factors and their unique receptor system is now beginning to be understood. Furthermore, analysis of mice lacking the genes for GDNF, neurturin, and their related receptors has confirmed the importance of these factors in neurodevelopment, The results of such analyses reveal numerous similarities and potential overlaps in the way the GDNF and the nerve growth factor (NGF) families regulate development of the peripheral nervous system.

关键词：果蝇蛋白质类胶质细胞源性神经营养因子胶质细胞源性神经营养因子受体配体小鼠基因敲除多基因族神经生长因子类/代谢神经组织蛋白质类/遗传学神经组织蛋白质类/代谢神经元/细胞学神经元/代谢副交感神经系统/细胞学副交感神经系统/胚胎学副交感神经系统/生长和发育周围神经系统/细胞学周围神经系统/胚胎学周围神经系统/生长和发育原癌基因蛋白质类/遗传学原癌基因蛋白质类/代谢原癌基因蛋白质c-ret 受体蛋白质酪氨酸激酶类/遗传学受体蛋白质酪氨酸激酶类/代谢交感神经系统/细胞学交感神经系统/胚胎学交感神经系统/生长和发育动物小鼠

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Ablation of P/Q-type Ca²⁺ channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α_1A-subunit

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第26期96卷 15245-15250页

作者： Jun, K Piedras-Renteria, ES Smith, SM Wheeler, DB Lee, SB Lee, TG Chin, HM Adams, ME Scheller, RH Tsien, RW Shin, HS Pohang Univ Sci & Technol Natl Creat Res Initiat Ctr Calcum & Learning Pohang 790784 South Korea Pohang Univ Sci & Technol Dept Life Sci Pohang 790784 South Korea Stanford Univ Sch Med Dept Mol & Cellular Physiol Stanford CA 94305 USA Stanford Univ Sch Med Howard Hughes Med Inst Stanford CA 94305 USA NIH Genet Res Branch Div Neurosci & Basic Behav Sci Bethesda MD 20892 USA Univ Calif Riverside Dept Entomol Riverside CA 92521 USA Univ Calif Riverside Dept Neurosci Riverside CA 92521 USA

The Ca2+ channel alpha(1A)-subunit is a voltage-gated, pore-forming membrane protein positioned at the intersection of two important lines of research: one exploring the diversity of Ca2+ channels and their physiological roles, and the other pursuing mechanisms of ataxia, dystonia, epilepsy, and migraine. alpha(1A)-Subunits are thought to support both P- and Q-type Ca2+ channel currents, but the most direct test, a null mutant, has not been described, nor is it known which changes in neurotransmission might arise from elimination of the predominant Ca2+ delivery system at excitatory nerve terminals. We generated alpha(1A)-deficient mice (alpha(1A)(-/-)) and found that they developed a rapidly progressive neurological deficit with specific characteristics of ataxia and dystonia before dying approximate to 3-4 weeks after birth. P-type currents in Purkinje neurons and P- and Q-type currents in cerebellar granule cells were eliminated completely whereas other Ca2+ channel types, including those involved in triggering transmitter release, also underwent concomitant changes in density. Synaptic transmission in alpha(1A)(-/-) hippocampal slices persisted despite the lack of P/Q-type channels but showed enhanced reliance on N-type and R-type Ca2+ entry. The alpha(1A)(-/-) mice provide a starting point for unraveling neuropathological mechanisms of human diseases generated by mutations in alpha(1A).

关键词：共济失调钙/代谢钙通道/缺乏钙通道/遗传学钙通道 N型钙通道 P型/代谢钙通道 Q型/代谢小脑/代谢导电性海马/代谢小鼠基因敲除神经组织蛋白质类/缺乏神经组织蛋白质类/遗传学神经系统疾病/病因学浦肯野细胞/代谢突触传递动物小鼠

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Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第6期97卷 2814-2819页

作者： Megonigal, MD Cheung, NKV Rappaport, EF Nowell, PC Wilson, RB Jones, DH Addya, K Leonard, DGB Kushner, BH Williams, TM Lange, BJ Felix, CA Univ Penn Abramson Res Ctr Div Oncol Childrens Hosp PhiladelphiaSch Med Philadelphia PA 19104 USA Univ Penn Sch Med Joseph Stokes Jr Res Inst Philadelphia PA 19104 USA Univ Penn Sch Med Dept Pediat Philadelphia PA 19104 USA Univ Penn Sch Med Dept Pathol & Lab Med Philadelphia PA 19104 USA Mem Sloan Kettering Canc Ctr Dept Pediat New York NY 10021 USA Univ Iowa Iowa City IA 52222 USA

Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors, How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia, The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation, The karyotypic del(11)(q23) was a cryptic t(11;17), GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed, The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia, MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.

关键词：抗肿瘤联合化疗方案/副作用碱基序列印迹法 DNA 染色体人 11对顺铂/副作用环磷酰胺/副作用 DNA结合蛋白质类/遗传学多柔比星/副作用依托泊甙/副作用外显子致命性结局组蛋白赖氨酸N-甲基转移酶白血病髓样/化学诱导白血病髓样/遗传学分子序列数据髓淋巴细胞性白血病蛋白质神经组织蛋白质类/遗传学神经母细胞瘤/药物疗法神经母细胞瘤/遗传学聚合酶链反应原癌基因时间因素拓扑异构酶II抑制剂转录因子易位遗传长春新碱/副作用青少年人类男(雄)性

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A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration

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NEURON 1999年第1期23卷 181-192页

作者： Hodgson, JG Agopyan, N Gutekunst, CA Leavitt, BR LePiane, F Singaraja, R Smith, DJ Bissada, N McCutcheon, K Nasir, J Jamot, L Li, XJ Stevens, ME Rosemond, E Roder, JC Phillips, AG Rubin, EM Hersch, SM Hayden, MR Univ British Columbia Ctr Mol Med & Therapeut Vancouver BC V5Z 4H4 Canada Univ British Columbia Dept Psychol Vancouver BC V6T 1Z4 Canada Univ Toronto Fac Pharm Toronto ON L4V 1V7 Canada Univ Toronto Dept Mol Immunol & Neurobiol Toronto ON M5G 1X5 Canada Emory Univ Sch Med Atlanta GA 30322 USA Univ Calif Berkeley Lawrence Berkeley Lab Ctr Human Genome Berkeley CA 94720 USA

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

关键词：适应生理学/生理学行为动物/生理学脑/病理学染色体人工酵母/遗传学纹状体/病理学细胞质/病理学疾病模型动物电生理学胚胎哺乳动物/生理学杭廷顿病/遗传学杭廷顿病/代谢杭廷顿病/病理学杭廷顿病/病理生理学小鼠近交系小鼠转基因/遗传学运动活动/生理学突变/生理学神经变性/病理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/代谢动物小鼠

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Characterization of the Schizosaccharomyces pombe orthologue of the human survival motor neuron (SMN) protein (vol 9, pg 675, 2000)

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HUMAN MOLECULAR GENETICS 2000年第7期9卷 1142-1142页

作者： Owen, N Doe, CL Mellor, J Davies, KE DepartmentofHumanAnatomyandGenetics UniversityofOxfordUK.

Childhood onset spinal muscular atrophy (SMA) is a common autosomal recessive disorder primarily characterized by the loss of lower motor neurons. The underlying chromosomal defects causing SMA have been found in the survival motor neuron (SMN) gene. SMN has been shown previously to play a role in both snRNP biogenesis and mRNA processing, although direct evidence for the relationship between SMN and disease pathology has not been elucidated. SMN orthologues have been isolated in many species including Caenorhabditis elegans and Danio rerio. To study the function of SMN, we have identified and characterized the Schizosaccharomyces pombe orthologue of human SMN, smn1+. We have demonstrated that smn1+ is essential for viability in *** and yeast expressing missense mutations in Smn1p, which mimic mutations in patients with Type I SMA, show significant mislocalization of the protein and a decrease in cell viability. Wild-type Smn1p is localized predominantly in the nucleus whereas yeast expressing Smn1p with missense mutations or deletions of specific domains of the protein accumulate cytoplasmic aggregates. Overexpression of Smn1p results in an increase in the growth rate of cells. Furthermore, mutations within two highly conserved protein interaction domains have a dominant-negative effect on growth, indicating that each domain is of functional significance in ***. These dominant phenotypes can be suppressed by overexpression of murine Smn in the same cell. Given the structural and functional similarities between the protein in fission yeast and higher eukaryotes, *** will be an ideal organism to study the role of SMN in RNA processing.

关键词：氨基酸序列碱基序列细胞核/代谢 cAMP反应元件结合蛋白质 DNA引物分子序列数据突变神经组织蛋白质类/化学神经组织蛋白质类/遗传学 RNA结合蛋白质类裂殖酵母菌属/遗传学序列同源性氨基酸动物人类

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Spinophilin regulates the formation and function of dendritic spines

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第16期97卷 9287-9292页

作者： Feng, J Yan, Z Ferreira, A Tomizawa, K Liauw, JA Zhuo, M Allen, PB Ouimet, CC Greengard, P Rockefeller Univ Mol & Cellular Neurosci Lab New York NY 10021 USA Northwestern Univ Dept Cell & Mol Biol NW Inst Neurosci Chicago IL 60611 USA Washington Univ Dept Anesthesiol Dept Anat & Neurobiol St Louis MO 63110 USA Florida State Univ Program Neurosci Tallahassee FL 32306 USA

Spinophilin, a protein that interacts with actin and protein phosphatase-1, is highly enriched in dendritic spines. Here, through the use of spinophilin knockout mice, we provide evidence that spinophilin modulates both glutamatergic synaptic transmission and dendritic morphology, The ability of protein phosphatase-1 to regulate the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors was reduced in spinophilin knockout mice. Consistent with altered glutamatergic transmission, spinophilin-deficient mice showed reduced long-term depression and exhibited resistance to kainate-induced seizures and neuronal apoptosis. In addition, deletion of the spinophilin gene caused a marked increase in spine density during development in vivo as well as altered filopodial formation in cultured neurons. In conclusion, spinophilin appears to be required for the regulation of the properties of dendritic spines.

关键词：细胞凋亡细胞培养的树突/生理学海马/解剖学和组织学海马/细胞学海马/生理学长时程增强小鼠基因敲除微丝蛋白质类/遗传学微丝蛋白质类/生理学神经组织蛋白质类/遗传学神经组织蛋白质类/生理学受体 AMPA/生理学受体 N-甲基-D-天冬氨酸/生理学动物小鼠

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Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene

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HUMAN MOLECULAR GENETICS 1999年第12期8卷 2317-2323页

作者： Chiurazzi, P Pomponi, MG Pietrobono, R Bakker, CE Neri, G Oostra, BA Univ Cattolica Ist Genet Med I-00168 Rome Italy Assoc Anni Verdi Ctr Ricerche Disabil Mentale & Motoria I-00168 Rome Italy Erasmus Univ Dept Clin Genet NL-3000 DR Rotterdam Netherlands Erasmus Univ Ctr Biomed Genet NL-3000 DR Rotterdam Netherlands

Most fragile X syndrome patients have expansion of a (CGG)(n) sequence with >200 repeats (full mutation) in the FMR1 gene responsible for this condition, Hypermethylation of the expanded repeat and of the FMR1 promoter is almost always present and apparently suppresses transcription, resulting in absence of the FMR1 protein. We recently showed that transcriptional reactivation of FMR1 full mutations can be achieved by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC). The level of histone acetylation is another important factor in regulating gene expression;therefore, we treated lymphoblastoid cell lines of non-mosaic full mutation patients with three drugs capable of inducing histone hyperacetylation, We observed a consistent, although modest, reactivation of the FMR1 gene with 4-phenylbutyrate, sodium butyrate and trichostatin A, as shown by RT-PCR, However, we report that combining these drugs with 5-azadC results in a 2- to 5-fold increase in FMR1 mRNA levels obtained with 5-azadC alone, thus showing a marked synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of FMR1 full mutations.

关键词：乙酰化作用阿扎胞苷/类似物和衍生物阿扎胞苷/药理学碱基序列细胞系 DNA甲基化 DNA引物酶抑制剂/药理学脆性X智力低下蛋白质脆性X综合征/遗传学组蛋白类/代谢神经组织蛋白质类/遗传学 RNA结合蛋白质类逆转录聚合酶链反应人类男(雄)性

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