微小RNA在tau蛋白过度磷酸化中的作用

阿尔茨海默病(Alzheimer’s Disease, AD)是一种慢性神经系统退行性疾病,AD的主要病理表现为脑组织中的老年斑和神经纤维缠结,老年斑的主要成分是异常积聚的β-淀粉样蛋白,过度磷酸化的tau蛋白是神经纤维缠结的主要成分。研究发现AD患者脑内微小RNA表达异常,且证据表明微小RNA参与β-淀粉样蛋白过量生成和tau蛋白过度磷酸化等Alzheimer样病理机制,在AD的发病中起着重要作用。本文就微小RNA在tau蛋白过度磷酸化中的作用及机制进行概述。     

G蛋白偶联受体对脑内Aβ代谢与功能的调节

阿尔茨海默病(Alzheimer's disease,AD)是一种神经退行性疾病,β-淀粉样蛋白(amyloidβ,Aβ)沉积和tau蛋白过度磷酸化是其主要病理特征。对AD发病机制的深入研究有助于寻找治疗AD的特异性药物。作为最大的膜蛋白家族,G蛋白偶联受体(G protein-coupled receptors,GPCRs)参与了AD的多个进程阶段。文章从GPCRs对Aβ合成的调节、Aβ毒性调节、Aβ降解、tau蛋白磷酸化,以及形成二聚体等方面阐述GPCRs参与AD发展的调控机制,有助于深入了解AD的发病机制,更好地研发以GPCRs为靶标的治疗AD的靶向性药物。     

Tau蛋白高度磷酸化致阿尔茨海默病动物模型研究进展

阿尔茨海默病（Alzheimer＇sdisease,AD）是老年人中最常见的神经退行性疾病,以过度磷酸化tau蛋白为核心形成的神经原纤维缠结为AD的主要病理特征之一。近年来对tau蛋白磷酸化的研究备受关注。在AD的实验研究中,探索理想的AD动物模型对于明确AD的病因、发病机制及药物的研发等方面起关键作用。本文对Tau蛋白磷酸化致AD主要动物模型的研究进展进行了综述,包括Tau转基因动物模型、激酶和磷酸化酶系统失衡致Tau蛋白过度磷酸化损伤模型、降低Tau蛋白糖基化致Tau过度磷酸化模型等。     

胰岛素降解酶在阿尔茨海默病发病机制中的研究进展

阿尔茨海默病（Alzheimer’s disease,AD）是一种以进行性认知功能减退为特征的神经退行性疾病。发病的确切机制尚未完全清楚。目前认为胰岛素抵抗与胰岛素信号系统受损是加速AD发病的危险因素,胰岛素降解酶（insulin-degrading enzyme,IDE）在糖代谢异常促使AD发病的过程中发挥重要的作用。除调节β淀粉样蛋白降解和清除之外,还可能通过调节tau蛋白磷酸化水平,协同载脂蛋白Ee4（ApoEe4）及影响胰岛素信号传导等参与AD的发病机制。本文就IDE生物学特性及在AD发病机制中的作用作一综述。     

阿尔茨海默病中Tau蛋白与线粒体损伤

阿尔茨海默病(Alzheimer’s disease, AD)是一种神经退行性疾病,过度磷酸化tau异常聚集形成的神经纤维缠结是其主要病理特征之一。线粒体损伤在AD发病机制中发挥重要作用,是AD的早期病理事件,而其又与tau蛋白密切相关。文中总结了AD中病理性tau蛋白对线粒体动力学、形态、自噬、功能等方面造成的损伤,并展望了从保护线粒体损伤角度研发防治AD药物的可行性。     

Tau 蛋白磷酸化在阿尔茨海默病中所处的地位

阿尔茨海默病(Alzheimer’s disease,AD)是一种老年人常见的神经系统退行性疾病,是痴呆最常见的病因。AD患者越来越多,给家属及社会带来严重负担造成了巨大的家庭和社会负担,这就迫使我们进一步探讨AD发病机制。在AD的众多发病机制中,tau蛋白假说倍受青睐。在蛋白磷酸酯酶2A(protein phosphatase 2A,PP2A)、糖原合酶激酶-3β(glycogen synthase kinase-3β,GSK-3β)、细胞周期依赖性蛋白激酶-5(cyclin-dependent kinase 5,CDK-5)和Bcl-2等蛋白酶及调节蛋白作用下,微管相关蛋白tau蛋白以其异常磷酸化结构或是形成二聚体、寡聚体和神经原纤维缠结等形式,参与到AD的病理过程。Tau蛋白及其相关结构,可能启动或促进了AD的凋亡,亦可能抑制了急性凋亡却促进了慢性的神经细胞变性。揭开这一谜底,可能揭开AD病理改变的神秘面纱。     

丝氨酸/苏氨酸蛋白磷酸酯酶在tau蛋白异常磷酸化中的作用

Tau蛋白过度磷酸化在阿尔采末病（Alzheimer’s disease,AD）发病过程中发挥重要作用,抑制蛋白磷酸酯酶活性,可诱导tau的过度磷酸化和聚积。本文拟就近年来蛋白磷酸酯酶在tau蛋白异常磷酸化中的作用作一综述。     

罗格列酮改善胰岛素抵抗大鼠海马Alzheimer病样tau蛋白磷酸化水平

Tau蛋白过度磷酸化是Alzheimer病(AD)发病的关键事件.由于2型糖尿病是AD的风险因子,并且胰岛素抵抗是2型糖尿病的特征,检测了胰岛素抵抗大鼠大脑海马tau蛋白磷酸化水平,以及运用胰岛素增敏剂罗格列酮(TZD)后磷酸化的变化,发现胰岛素抵抗组大鼠海马tau蛋白呈过度磷酸化改变,但运用TZD后,tau蛋白的磷酸化状态有所恢复.由于糖原合成激酶-3β(GSK-3β)位于胰岛素信号转导途径中,并且是tau蛋白的重要磷酸激酶,研究检测罗格列酮干预前后GSK-3β活性,发现均升高.研究结果表明,肥胖时胰岛素抵抗导致细胞内胰岛素信号转导途径中,GSK-3β活性上调可能是引起大鼠海马内tau蛋白过度磷酸化的一个重要原因;虽然TZD可抑制tau蛋白的过度磷酸化,但可能不是通过下调GSK-3β活性的途径.     

APP/PS1转基因鼠脑内小泛素化修饰物-1上调可能参与阿尔茨海默病老年斑形成和神经突起变性的调节北大核心CSCD

小泛素化修饰物(small ubiquitin-related modifier,SUMO)是一类重要的类泛素蛋白,研究显示一些神经退行性疾病相关蛋白可以被SUMO化修饰。本文旨在观察APP/PS1转基因阿尔茨海默病(Alzheimer’s disease,AD)鼠中SUMO-1表达及修饰的变化,并探讨SUMO-1与AD病理的关系。采用免疫印迹的方法检测12月龄的APP/PS1转基因AD鼠脑内SUMO-1表达及修饰的变化,同时用免疫共沉淀及免疫荧光的方法研究AD鼠脑内SUMO-1与tau、APP和Aβ的关系。结果显示:(1)与正常野生型小鼠相比,AD鼠脑内SUMO-1表达及其修饰的蛋白增加,同时伴有泛素化蛋白的增加;(2)AD鼠大脑皮层的RIPA可溶蛋白组份中,SUMO-1修饰的tau增加,而AT8抗体识别的磷酸化tau的SUMO-1修饰减少,但422位点磷酸化tau的SUMO-1修饰没有明显改变;(3)SUMO-1与磷酸化tau、APP及Aβ免疫荧光双标显示,在AD鼠脑内SUMO-1可在老年斑的中部和周围分布,并且SUMO-1与AT8识别的磷酸化tau在老年斑周围的变性神经突起中有相对较多的共存,但与APP、PS422识别的磷酸化tau和Aβ的共定位很少。以上结果提示,SUMO-1在APP/PS1转基因AD小鼠脑内表达增加,并可能参与变性神经突起及老年斑形成的调节。     

褪黑素对异丙肾上腺素诱导大鼠tau蛋白过度磷酸化的预防作用

异常过度磷酸化的微管相关蛋白tau是阿尔茨海默病(Alzheimer's disease,AD)患者大脑中神经原纤维缠结的主要组成部分.迄今为止,尚无有效的措施阻止tau蛋白的过度磷酸化.为探讨褪黑素(melatonin,Mel)对AD样tau蛋白过度磷酸化的预防作用,我们以β受体激动剂异丙肾上腺素(isoproterenol,IP)来复制AD样tau蛋白过度磷酸化的动物模型,在大鼠双侧海马注射IP前,以褪黑素作为保护组药物,于腹腔连续注射5 d.应用磷酸化位点特异性抗体(PHF-1和Tau-1)作免疫印迹和免疫组织化学检测tau蛋白的磷酸化水平,并用非磷酸化依赖的总tau蛋白抗体(111e)进行标准化.免疫印迹结果显示在注射IP 48 h后,tau蛋白在PHF-1表位的免疫反应显著增强,在Tau-1表位显著减弱,表明tau蛋白在Ser396/Ser404(PHF-1)和Ser199/Ser202(Tau-1)位点有过度磷酸化.免疫组织化学染色结果与免疫印迹结果相似,主要检测到在大鼠海马CA3区的神经纤维有tau蛋白过度磷酸化.褪黑素预处理大鼠可有效地阻止IP诱导tau蛋白在Tau-1和PHF-1位点的过度磷酸化.上述结果提示褪黑素可预防大鼠脑组织中由异丙肾上腺素引起的AD样tau蛋白的过度磷酸化.     

Building arks for tRNA: Structure and function of the Arc1p family of non-catalytic tRNA-binding proteins

Following the intricate architecture of the eukaryotic cell, protein synthesis involves formation of many macromolecular assemblies, some of which are composed by tRNA-aminoacylation enzymes. Protein-protein and protein-tRNA interactions in these complexes can be facilitated by non-catalytic tRNA-binding proteins. This review focuses on the dissection of the molecular, structural and functional properties of a particular family of such proteins: yeast Arc1p and its homologues in prokaryotes and higher eukaryotes. They represent paradigms of the strategies employed for the organization of sophisticated and dynamic nanostructures supporting spatio-temporal cellular organization.     

Biological functions of p53 isoforms through evolution: lessons from animal and cellular models

The TP53 tumour-suppressor gene is expressed as several protein isoforms generated by different mechanisms, including use of alternative promoters, splicing sites and translational initiation sites, that are conserved through evolution and within the TP53 homologues, TP63 and TP73. Although first described in the eighties, the importance of p53 isoforms in regulating the suppressive functions of p53 has only become evident in the last 10 years, by analogy with observations that p63 and p73 isoforms appeared indispensable to fully understand the biological functions of TP63 and TP73. This review summarizes recent advances in the field of 'p53 isoforms', including new data on p63 and p73 isoforms. Details of the alternative mechanisms that produce p53 isoforms and cis- and trans-regulators identified are provided. The main focus is on their biological functions (apoptosis, cell cycle, aging and so on) in cellular and animal models, including mouse, zebrafish and Drosophila. Finally, the deregulation of p53 isoform expression in human cancers is reviewed. Based on these latest results, several developments are expected in the future: the identification of drugs modulating p53 isoform expression; the generation of animal models and the evaluation of the use of p53 isoform as biomarkers in human cancers.     

The Ndc80p complex from Saccharomyces cerevisiae contains conserved centromere components and has a function in chromosome segregation

We have purified a complex from Saccharomyces cerevisiae containing the spindle components Ndc80p, Nuf2p, Spc25p, and Spc24p. Temperature-sensitive mutants in NDC80, SPC25, and SPC24 show defects in chromosome segregation. In spc24-1 cells, green fluorescence protein (GFP)-labeled centromeres fail to split during spindle elongation, and in addition some centromeres may detach from the spindle. Chromatin immunoprecipitation assays show an association of all four components of the complex with the yeast centromere. Homologues of Ndc80p, Nuf2p, and Spc24p were found in Schizosaccharomyces pombe and GFP tagging showed they were located at the centromere. A human homologue of Nuf2p was identified in the expressed sequence tag database. Immunofluorescent staining with anti-human Nuf2p and with anti-HEC, the human homologue of Ndc80p, showed that both proteins are at the centromeres of mitotic HeLa cells. Thus the Ndc80p complex contains centromere-associated components conserved between yeasts and vertebrates.     

Regulation of the Activity in the p53 Family Depends on the Organization of the Transactivation Domain

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Twice switched at birth: cell cycle-independent roles of the "neuron-specific" cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells

Cdk5 (cyclin-dependent kinase 5 or initially NCLK for neuronal CDC2-like kinase) was switched twice at its birth nearly twenty years ago: first it was thought to be cyclin-dependent, second it was assumed to be primarily of importance in neuronal cells—both turned out not to be the case. In this review we want to discuss issues of pharmacological inhibition, to highlight the versatile roles, and to summarize the growing evidence for the functional importance of Cdk5 in non-neuronal tissues, such as blood cells, tumor cells, epithelial cells, the vascular endothelium, testis, adipose and endocrine tissues. The organizing principles we follow are apoptosis/cell death, migration/motility, aspects of inflammation, and, finally, secretion/metabolism.