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A microtiter plate assay for polyglutamine aggregate extension

ANALYTICAL BIOCHEMISTRY 2001年第2期295卷 227-236页

作者： Berthelier, V Hamilton, JB Chen, SM Wetzel, R Univ Tennessee Med Ctr Grad Sch Med Knoxville TN 37920 USA

Polyglutamine (polyGln) aggregates are neuropathological markers of expanded CAG repeat disorders, and may also play a critical role in the development of these diseases. We have established a highly sensitive, fast, reproducible, and specific assay capable of monitoring aggregate-dependent deposition of polyglutamine peptides. This assay allows detailed studies on various aspects of aggregation kinetics, and also makes possible the detection and quantitation of low levels of "extension-competent" aggregates. In the simplest form of this assay, polyGln aggregates are made from chemically synthesized peptides and immobilized onto microplate wells. These wells are incubated for different times with low concentrations of a soluble biotinylated polyGln peptide. Europium-streptavidin complexation of the immobilized biotin, followed by time-resolved fluorescence detection of the deposited europium, allows us to calculate the rate (fmol/h) of incorporation of polyGln peptides into polyGln aggregates. This assay will make possible basic studies on the assembly mechanism of polyGln aggregates and on critical features of the reaction, such as polyGln length dependence. The assay also will be a valuable tool for screening and characterizing antiaggregation inhibitors. It will also be useful for detection and quantitation of aggregation-competent polyGln aggregates in biological materials, which may prove to be of critical importance in understanding the disease mechanism. (C) 2001 Academic Press.

关键词：动力学方法神经变性疾病/代谢肽类/分析肽类/化学合成肽类/代谢可重复性结果人类

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Metabolism and functions of glutathione in brain

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PROGRESS IN NEUROBIOLOGY 2000年第6期62卷 649-671页

作者： Dringen, R Univ Tubingen Inst Physiol Chem D-72076 Tubingen Germany

The tripeptide glutathione is the thiol compound present in the highest concentration in cells of all organs. Glutathione has many physiological functions including its involvement in the defense against reactive oxygen species. The cells of the human brain consume about 20% of the oxygen utilized by the body but constitute only 2% of the body weight. Consequently, reactive oxygen species which are continuously generated during oxidative metabolism will be generated in high rates within the brain. Therefore. the detoxification of reactive oxygen species is an essential task within the brain and the involvement of the antioxidant glutathione in such processes is very important. The main focus of this review article will be recent results on glutathione metabolism of different brain cell types in culture. The glutathione content of brain cells depends strongly on the availability of precursors for glutathione. Different types of brain cells prefer different extracellular glutathione precursors. Glutathione is involved in the disposal of peroxides by brain cells and in the protection against reactive oxygen species. In coculture astroglial cells protect other neural cell types against the toxicity of various compounds. One mechanism for this interaction is the supply by astroglial cells of glutathione precursors to neighboring cells. Recent results confirm the prominent role of astrocytes in glutathione metabolism and the defense against reactive oxygen species in brain. These results also suggest an involvement of a compromised astroglial glutathione system in the oxidative stress reported for neurological disorders. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：星形细胞/细胞学星形细胞/代谢生物转运/生理学脑/代谢细胞间通讯/生理学细胞培养的细胞外隙/代谢谷胱甘肽/缺乏谷胱甘肽/代谢小神经胶质细胞/细胞学小神经胶质细胞/代谢神经变性疾病/代谢神经元/细胞学神经元/代谢少突神经胶质/细胞学少突神经胶质/代谢氧化还原活性氧/代谢动物人类

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Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions

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SCIENCE 2000年第5493期290卷 985-989页

作者： Giasson, BI Duda, JE Murray, IVJ Chen, QP Souza, JM Hurtig, HI Ischiropoulos, H Trojanowski, JQ Lee, VMY Univ Penn Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Dept Neurol Philadelphia PA 19104 USA Childrens Hosp Philadelphia Dept Biochem & Biophys Philadelphia PA 19104 USA Stokes Res Inst Philadelphia PA 19104 USA

Aggregated alpha -synuclein proteins form brain Lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha -synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha -synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha -synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha -synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

关键词：阿尔茨海默病/代谢阿尔茨海默病/病理学抗体单克隆印迹法蛋白质脑/代谢脑/病理学脑化学酶联免疫吸附测定荧光抗体技术免疫组织化学 Lewy体/化学 Lewy体病/代谢 Lewy体病/病理学显微镜检查免疫电子多系统萎缩/代谢多系统萎缩/病理学神经组织蛋白质类/分析神经组织蛋白质类/免疫学神经组织蛋白质类/代谢神经变性疾病/代谢神经变性疾病/病理学神经元/化学神经元/代谢神经元/超微结构氧化性应激帕金森病/代谢帕金森病/病理学突触核蛋白类酪氨酸/类似物和衍生物酪氨酸/分析酪氨酸/免疫学酪氨酸/代谢 α突触核蛋白人类

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Distribution and retrograde transport of trophic factors in the central nervous system: Functional implications for the treatment of neurodegenerative diseases

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PROGRESS IN NEUROBIOLOGY 1999年第4期57卷 451-484页

作者： Mufson, EJ Kroin, JS Sendera, TJ Sobreviela, T Rush Presbyterian St Lukes Med Ctr Rush Alzheimers Dis Ctr Res Ctr Brain Repair Dept Neurol Sci Chicago IL 60612 USA Rush Presbyterian St Lukes Med Ctr Rush Alzheimers Dis Ctr Res Ctr Brain Repair Dept Neurosurg Chicago IL 60612 USA

Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intra-parenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde trans port of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pens. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. (C) 1999 Elsevier Science Ltd. All rights reserved.

关键词：轴突运输中枢神经系统/细胞学中枢神经系统/代谢中枢神经系统/病理学成纤维细胞生长因子/投药和剂量成纤维细胞生长因子/代谢神经生长因子类/投药和剂量神经生长因子类/代谢神经生长因子类/药理学神经组织蛋白质类/投药和剂量神经组织蛋白质类/代谢神经组织蛋白质类/药理学神经变性疾病/代谢神经变性疾病/治疗受体神经生长因子类/代谢动物人类

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Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第19期96卷 10812-10817页

作者： Harris, ZL Durley, AP Man, TK Gitlin, JD Washington Univ Sch Med Edward Mallinckrodt Dept Pediat St Louis MO 63110 USA

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism, Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although normal at birth, Cp-/- mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to Q-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes, Ferrokinetic studies in Cp+/+ and Cp-/- mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp-/- mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.

关键词：脱辅蛋白质类/代谢血浆铜蓝蛋白/缺乏血浆铜蓝蛋白/遗传学血浆铜蓝蛋白/代谢血浆铜蓝蛋白/生理学疾病模型动物内环境稳定铁/血液铁/代谢铁/药代动力学肝/解剖学和组织学肝/代谢金属代谢缺陷先天性/遗传学金属代谢缺陷先天性/代谢模型遗传学诱变插入神经变性疾病/遗传学神经变性疾病/代谢表型脾/解剖学和组织学脾/代谢时间因素动物小鼠

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Implications of macromolecular crowding for protein assembly

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CURRENT OPINION IN STRUCTURAL BIOLOGY 2000年第1期10卷 34-39页

作者： Minton, AP NIDDKD Lab Biochem & Genet Sect Phys Biochem NIH Bethesda MD 20892 USA

Recent studies have led to increased appreciation of the influence of excluded volume in solutions of high total macromolecular content ('macromolecular crowding') upon the various classes of reaction that lead to the assembly of proteins and protein complexes. In general, crowding is expected to stabilize native protein structure relative to less compact non-native structures and to favor the formation of functional complexes of native proteins. Under certain pathological conditions, 'overcrowding' may enhance the formation of nonfunctional aggregates of non-native protein (e.g, amyloid and inclusion bodies).

关键词：腺苷三磷酸/生理学淀粉样蛋白/代谢生物聚合物细胞大小大分子物质模型生物学神经变性疾病/代谢肽类/化学蛋白质构象蛋白质折叠动物人类

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Zn²⁺:: A novel ionic mediator of neural injury in brain disease (vol 21, pg 395, 2000)

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TRENDS IN PHARMACOLOGICAL SCIENCES 2000年第12期21卷 496-496页

作者： Weiss, JH Sensi, SL Koh, JY UniversityofCalifornia IrvineCA92697-4292USA.jweiss@uci.edu

Zn2+ is the second most prevalent trace element in the body and is present in particularly large concentrations in the mammalian brain. Although Zn^2+ is a cofactor for many enzymes in all tissues, a unique feature of brain Zn^2+ is its vesicular localization in presynaptic terminals, where its release is dependent on neural activity. Although the physiological significance of synaptic Zn^2+ release is little understood, it probably plays a modulatory role in synaptic transmission. Furthermore, several lines of evidence support the idea that, upon excessive synaptic Zn^2+ release, its accumulation in postsynaptic neurons contributes to the selective neuronal loss that is associated with certain acute conditions, including epilepsy and transient global ischaemia. More speculatively, Zn^2+ dis-homeostasis might also contribute to some degenerative conditions, including Alzheimer's disease. Further elucidation of the pathological actions of Zn^2+ in the brain should result in new therapeutic approaches to these conditions.

关键词：脑疾病/代谢钙通道/代谢神经变性疾病/病因学神经变性疾病/代谢神经元/代谢突触前末梢/代谢受体 N-甲基-D-天冬氨酸/代谢信号传导/生理学锌/代谢锌/生理学动物人类

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Cortical degeneration in the absence of neurotrophin signaling: Dendritic retraction and neuronal loss after removal of the receptor TrkB

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NEURON 2000年第1期26卷 233-245页

作者： Xu, BJ Zang, KL Ruff, NL Zhang, YA McConnell, SK Stryker, MP Reichardt, LF Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94143 USA Univ Calif San Francisco Dept Physiol San Francisco CA 94143 USA Stanford Univ Dept Sci Biol Stanford CA 94305 USA

To examine functions of TrkB in the adult CNS, TrkB has been removed from neurons expressing CaMKII, primarily pyramidal neurons, using Cre-mediated recombination. A floxed trkB allele was designed so that neurons lacking TrkB express tau-beta-galactosidase. Following trkB deletion in pyramidal cells, their dendritic arbors are altered, and cortical layers II/III and V are compressed, after which there is an apparent loss of mutant neurons expressing the transcription factor SCIP but not of those expressing Otx-1. Loss of neurons expressing SCIP requires deletion of trkB within affected neurons;reduction of neuronal ER81 expression does not, suggesting both direct and indirect effects of TrkB loss. Thus, TrkB is required for the maintenance of specific populations of cells in the adult neocortex.

关键词：细胞计数 DNA结合蛋白质类/代谢树突/代谢树突/病理学小鼠转基因突变/遗传学新皮质/代谢新皮质/病理学神经生长因子类/代谢神经变性疾病/代谢神经变性疾病/病理学神经元/代谢神经元/病理学锥体细胞/代谢受体 trkB/遗传学受体 trkB/代谢转录因子/代谢 β半乳糖苷酶类/代谢动物小鼠

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Redox metals and neurodegenerative disease

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CURRENT OPINION IN CHEMICAL BIOLOGY 1999年第2期3卷 220-225页

作者： Sayre, LM Perry, G Smith, MA Case Western Reserve Univ Dept Chem Cleveland OH 44106 USA Case Western Reserve Univ Dept Pathol Cleveland OH 44106 USA

Multiple lines of evidence implicate redox-active transition metals as mediators of oxidative stress in neurodegenerative diseases. Among the recent research discoveries is the finding that transition metals bind to proteins associated with neurodegeneration, including the prion protein. Whereas binding in the latter case may serve an antioxidant function, adventitious binding of metals to other proteins appears to preserve their catalytic redox activity in a manner that disturbs free radical homeostasis. Alterations in the levels of copper- and iron-containing metalloenzymes, involved in processing partially reduced oxygen species, are also likely to contribute to altered redox balance in neurodegenerative diseases. Nonetheless, even in familial forms of amyotrophic lateral sclerosis linked to mutations in superoxide dismutase, it is unclear whether an altered enzyme activity or, indirectly, a disturbance in transition-metal homeostasis is involved in the disease pathogenesis.

关键词：淀粉样β蛋白/代谢内环境稳定金属/代谢神经变性疾病/酶学神经变性疾病/代谢氧化还原氧化性应激超氧化物歧化酶/代谢人类

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Nitration of tau protein is linked to neurodegeneration in tauopathies

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AMERICAN JOURNAL OF PATHOLOGY 2003年第3期163卷 1021-1031页

作者： Horiguchi, T Uryu, K Giasson, BI Ischiropoulos, H LightFoot, R Bellmann, C Richter-Landsberg, C Lee, VMY Trojanowski, JQ Univ Penn Sch Med Dept Pathol & Lab Med Ctr Neurodegenerat Dis ResInst Aging Philadelphia PA 19104 USA Childrens Hosp Philadelphia Dept Biochem & Biophys Philadelphia PA USA Univ Penn Philadelphia PA 19104 USA Carl von Ossietzky Univ Oldenburg Dept Biol Oldenburg Germany

Oxidative and nitrative injury is implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome (DS\), but no direct evidence links this type of injury to the formation of neurofibrillary tau lesions. To address this, we generated a monoclonal antibody (mAb), n847, which recognizes nitrated tau and a-synuclein. n847 detected nitrated tau in the insoluble fraction of AD, corticobasal degeneration (CBD), and Pick's disease (PiD) brains by Western blots. Immunohistochemistry (IHC) showed that n847 labeled neurons in the hippocampus and neocortex of AD and DS brains. Double-label immunofluorescence with n847 and an anti-tau antibody revealed partial co-localization of tau and n847 positive tangles, while n847 immmunofluorescence and Thioflavin-S double-staining showed that a subset of n847-labeled neurons were Thioflavin-S-positive. In addition, immuno-electron microscopy revealed that tau-positive filaments in tangle-bearing neurons were also labeled by n847 and IHC of other tauopathies showed that some of glial and neuronal tau pathologies in CBD, progressive supranuclear palsy, PiD, and frontotemporal dementia with parkinsonism linked to chromosome 17 also were n847-positive. Finally, nitrated and Thioflavin-S-positive tau aggregates were generated in a oligodendrocytic cell line after treatment with peroxynitrite. Taken together, these findings imply that nitrative injury is directly linked to the formation of filamentous tau inclusions.

关键词：阿尔茨海默病/代谢阿尔茨海默病/病理学基底神经节细胞系大脑皮质唐氏综合征/代谢唐氏综合征/病理学荧光染料神经变性/病因学神经变性疾病/代谢神经变性疾病/病理学神经原纤维缠结/代谢硝酸盐类/代谢脑皮克病/代谢脑皮克病/病理学 Tau病变/并发症 Tau病变/代谢噻唑类组织分布 tau蛋白质类/代谢老年人老年人 80以上女(雌)性人类男(雄)性中年人

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