Caspase与神经系统疾病

近年来,细胞凋亡发生机制的研究已取得众多进展。研究表明,许多神经系统疾病与caspase家族有着密切联系。现将细胞凋亡的最新研究结果及其与神经系统疾病的关系,尤其是caspase家族在神经系统疾病中的主导地位作简单综述,希望由此了解神经元细胞凋亡的内在机制并达到治疗目的。     

胆固醇代谢异常与神经系统疾病关系的研究进展

胆固醇是一种广泛存在于动物体内的常见小分子脂类物质,是构成细胞膜和血浆脂蛋白的重要成分。其在中枢神经系统内的含量尤为丰富,与神经元突起的产生、发育和形成,星形胶质细胞的增生,神经元的存活,神经的修复重塑以及发育相关的信号通路的传递等活动紧密相关。由于血脑屏障的隔离,脑内胆固醇主要由星形胶质细胞合成,其代谢需要通过转化为可透过血脑屏障的分子才能排出脑外。正常情况下,脑内胆固醇的浓度维持在相对稳定的范围内,对中枢神经系统的生长发育以及正常功能的维持起着至关重要的作用,其代谢异常可以诱多种神经系统疾病,因此以维持脑内胆固醇代谢的稳态为靶标可以为许多神经系统疾病的防治提供新思路。本文综述了脑内胆固醇的合成、代谢以及其与中枢神经系统疾病的相关性。     

微囊蛋白基因及其与疾病关系研究进展

微囊蛋白(caveolin)基因家族已鉴定出3个成员:微囊蛋白-1、微囊蛋白-2、微囊蛋白-3,并被定位于抑癌基因位点区域.微囊蛋白-1是细胞质膜微囊的标记蛋白,其中间疏水区域在细胞膜内形成发夹结构,并使其N端区域与C端区域在细胞膜内表面聚合形成支架结构.微囊蛋白-1与微囊蛋白-2以组成异源寡聚体的形式存在,在脂肪细胞、内皮细胞和成纤维细胞中表达最丰富,微囊蛋白-3则特异表达于肌肉.离体与活体研究结果均表明微囊蛋白-1可能具有抑癌功能,并可能在细胞信号传导中起刹车作用.微囊蛋白-1基因敲除小鼠心血管NO与Ca²⁺信号途径受损、功能异常,肺泡上皮细胞出现异常扩增,脂质代谢失衡,身体消瘦.微囊蛋白-2基因敲除小鼠肺功能与耐力均严重受损,与微囊蛋白-1基因敲除小鼠的表型非常相似.微囊蛋白-3为维持心脏正常功能所必需,可能还与一些肌肉营养不良症有关.     

线粒体与神经系统退行性疾病

现在普遍认为线粒体是控制凋亡的中心 ,线粒体功能的失调可以导致许多神经系统退行性疾病的发生。神经元死亡是一些神经系统退行性疾病的共同特征 ,其中包括帕金森氏病 (ＰＤ)、阿尔茨海默病(ＡＤ)、亨廷顿舞蹈病 (ＨＤ)以及肌萎缩型侧索硬化症(ＡＬＳ)等 ,这些疾病的遗传因素和环境因素现已得到确认 ,其中包括氧化应激 ,Ｃａ2 平衡失调 ,线粒体的功能失调以及胱天蛋白酶 (ｃａｓｐａｓｅ)的激活。研究促进或抑制神经元凋亡的机制可以为预防和治疗神经系统退行性疾病提供新的思路和方法。在一些哺乳动物不同类型的衰老细胞中已发现线粒体膜…     

PDCD5基因及其与疾病的关系

程序化死亡因子5基因(PDCD5)是北京大学人类疾病基因研究中心从白血病细胞株TF-1细胞中克隆的新基因。已有研究表明,PDCD5是促进细胞凋亡的基因,参与许多凋亡异常相关疾病的形成,并与其病程进展密切相关。该文介绍PDCD5的结构、功能及其与肿瘤等疾病的关系。     

人类驱动结合蛋白及其与某些疾病的相关性

驱动结合蛋白（Kinectin）是真核细胞内生物进化上的保守蛋白质,已发现的功能有（1）与驱动蛋白（Kinesin）相连参与细胞胞吐、胞质运输和有丝分裂等活动;（2）是RhoG蛋白依赖微管的细胞内活动的效应物;（3）是整合素依赖的黏附分子复合体的重要组分;（4）转录延长因子-I通过与驱动结合蛋白结合锚着于内质网,发挥相应的生物学作用。随着研究的深入,发现人类驱动结合蛋白与某些疾病如甲状腺癌、白塞病、再生障碍性贫血、肝细胞癌有一定的相关性。     

BAG-1蛋白及其对神经系统疾病调控研究进展

B细胞CLL/淋巴瘤2关联凋亡基因1（B-cell CLL/lymphoma 2-associated athanogene-1,BAG-1）编码的蛋白是一种多功能结合蛋白,包含不同功能的结构域,可与抗凋亡蛋白（Bcl-2）、热激蛋白70（heat shock protein 70,Hsp70/Hsc70）、细胞转化分裂介质（Raf-1）、类固醇激素受体和DNA等结合,对于调节细胞凋亡、信号传导、基因转录、细胞增殖与分化等具有重要作用。BAG-1参与多种神经系统疾病（如阿尔茨海默病、帕金森氏病、亨廷顿舞蹈病、脑中风、脊髓损伤以及神经精神障碍疾病）的发生发展过程。主要就BAG-1的结构、功能及其对神经系统疾病影响的研究进展进行了综述,以期为神经系统疾病的研究和治疗提供参考。     

S100B蛋白在神经系统疾病中的临床意义及进展

S100B蛋白是主要由神经胶质细胞分泌的一种钙结合蛋白,在生理浓度下,S100B蛋白具有旁分泌或自分泌神经营养作用,高浓度时则具有神经毒害作用。脑脊液、血液、尿液、唾液、羊水等体液中S100B蛋白水平的升高被认为是多种疾病的生物学指标,如急性脑损伤、围产期脑损伤、脑肿瘤、神经系统炎症性或退行性疾病,精神疾病等。S100B蛋白不仅仅是一种生物学指标,也可作为疾病治疗的靶向目标。目前存在的主要问题是,S100B蛋白主要由受损细胞渗漏,还是病理生理条件下分泌的S100B蛋白造成了细胞损伤。本文就S100B蛋白在神经科疾病中的诊断、治疗及新进展做一综述,并提出进一步研究的设想。     

T、B淋巴细胞的凋亡及其与疾病的关系

细胞凋亡是免疫系统的一个重要的事件,它凋控着淋巴细胞的成熟、受体组分的选择及内环境的稳定。其中T、B淋巴细胞在各自的发育过程中都发生大量的细胞凋亡。Fas/FasL信号途径、NoTCH信号途径是免疫系统细胞凋亡的两条最主要的途径。此外,一些共刺激分子（如CD40）在T、B淋巴细胞存活及凋亡的选择上也发挥着重要作用。凋亡同细胞的生长、分化一样,对免疫细胞发挥正常功能是必不可少的。因此,免疫系统细胞凋亡的脱轨势必会给机体带来严重的影响,导致一系列相关疾病的发生。     

钙离子结合蛋白及其在神经系统疾病中的作用

钙离子作为第二信使参与多种途径的调控,钙离子结合蛋白在此过程中起着重要的作用．通过对钙离子结合蛋白的分布特征、结构分析,新的成员以及新的功能不断地被发现．在疾病发生过程中,钙离子结合蛋白动态平衡的破坏与线粒体的异常、自由基的损害有密切的关系,并已在多种疾病特别是神经系统的疾病中得到了证实．本文就钙离子结合蛋白的特征以及在主要神经系统疾病中作用的研究进展进行简要综述．     

RNA-binding proteins in neurological diseases

Emerging studies support that RNA-binding proteins(RBPs)play critical roles in human biology and pathogenesis.RBPs are essential players in RNA processing and metabolism,including pre-mRNA splicing,polyadenylation,transport,surveillance,mRNA localization,mRNA stability control,translational control and editing of various types of RNAs.Aberrant expression of and mutations in RBP genes affect various steps of RNA processing,altering target gene function.RBPs have been associated with various diseases,including neurological diseases.Here,we mainly focus on selected RNA-binding proteins including Nova-1/Nova-2,HuR/HuB/HuC/HuD,TDP-43,Fus,Rbfox1/Rbfox2,QKI and FMRP,discussing their function and roles in human diseases.     

Rab蛋白家族在神经类疾病中的作用

细胞内膜囊泡运输是一个复杂的通路网络,Rab GTPases是膜囊泡运输的主要调节剂,通常被认为是细胞内吞和分泌系统中各种细胞器和囊泡的特异性标记和识别物。与Rab蛋白相关的轴突运输、内体运输发生障碍是造成神经退行性疾病的重要原因之一。本文主要介绍了Rab蛋白在多种神经退行性疾病病理机制中的作用机理与调控机制,同时讨论了线粒体和胶质细胞功能异常与Rab蛋白之间的关联。深入探究Rab蛋白的作用机制对人类神经性疾病的早期诊断和治疗具有潜在的指导意义。     

Raf激酶抑制蛋白在信号传导通路及凋亡中的关键作用

细胞维持自身的完整性存在众多调控,避免它从一个生物学状态到另一个状态随意的转换。Raf激酶抑制蛋白（Rafkinase inhibitor protein,RKIP）,属于磷脂酰乙醇胺结合蛋白（phosphatidylethanolamine binding protein,PEBP）家族的成员,是新的一类信号级联传导的调节器来维持细胞自身平衡。RKIP可以抑制MAP激酶途径（Raf-1／MEK／ERK）,G蛋白偶联途径（G—protein coupled receptor,GPCR）,以及NF-κb途径。正因为RKIP在这些信号传导中的作用,使其在细胞凋亡过程中发挥了关键性的作用。更加深入的了解RKIP如何在肿瘤细胞调控表达,了解它如何对细胞凋亡、信号传导产生影响可以为人类治疗癌症起到极大的推动作用。     

5-羟甲基胞嘧啶及其TET氧合酶在神经系统发育和相关疾病中的研究进展

神经系统的正常发育是多种因素相互协调作用的结果,一旦特定因素失衡将引起相关疾病的发生。近年来不断有研究发现,DNA去甲基化过程的一类中间产物5-羟甲基胞嘧啶(5-hydroxymethylcytosine, 5hmC)作为一种新的表观遗传标记,在神经系统中高水平分布,并参与认知、记忆等重要的神经功能。5hmC的形成由氧合酶家族分子(ten-eleven translocation protein, TET)催化,在多种神经系统相关疾病中,5hmC水平和TETs分子的表达都发生改变,提示TET-5hmC表观遗传机制在复杂的神经系统发生发展过程中发挥了重要的调控作用。此外,作为基因表达调控的DNA标记物,5hmC的基因定位与基因表达水平的关系也是重要的研究方向。本文就近年来5hmC和TET家族蛋白分子在神经系统发育和相关疾病方面的重要研究发现进行了综述总结,希望为相关领域研究人员深入开展研究提供重要的思路,并为相关疾病设计治疗策略提供理论支持。     

Redox-based endoplasmic reticulum dysfunction in neurological diseases

The redox homeostasis of the endoplasmic reticulum lumen is characteristically different from that of the other subcellular compartments. The concerted action of membrane transport processes and oxidoreductase enzymes maintain the oxidized state of the thiol-disulfide and the reducing state of the pyridine nucleotide redox systems, which are prerequisites for the normal functions of the organelle. The powerful thiol-oxidizing machinery allows oxidative protein folding but continuously challenges the local antioxidant defense. Alterations of the cellular redox environment either in oxidizing or reducing direction affect protein processing and may induce endoplasmic reticulum stress and unfolded protein response. The activated signaling pathways attempt to restore the balance between protein loading and processing and induce apoptosis if the attempt fails. Recent findings strongly support the involvement of this mechanism in brain ischemia, neuronal degenerative diseases and traumatic injury. The redox changes in the endoplasmic reticulum are integral parts of the pathomechanism of neurological diseases, either as causative agents, or as complications.     

Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state-of-the-art

Neural stem cells (NSCs) are multipotent stem cells with remarkable self-renewal potential and also unique competencies to differentiate into neurons, astrocytes, and oligodendrocytes (ODCs) and improve the cellular microenvironment. In addition, NSCs secret diversity of mediators, including neurotrophic factors (e.g., BDNF, NGF, GDNF, CNTF, and NT-3), pro-angiogenic mediators (e.g., FGF-2 and VEGF), and anti-inflammatory biomolecules. Thereby, NSCs transplantation has become a reasonable and effective treatment for various neurodegenerative disorders by their capacity to induce neurogenesis and vasculogenesis and dampen neuroinflammation and oxidative stress. Nonetheless, various drawbacks such as lower migration and survival and less differential capacity to a particular cell lineage concerning the disease pathogenesis hinder their application. Thus, genetic engineering of NSCs before transplantation is recently regarded as an innovative strategy to bypass these hurdles. Indeed, genetically modified NSCs could bring about more favored therapeutic influences post-transplantation in vivo, making them an excellent option for neurological disease therapy. This review for the first time offers a comprehensive review of the therapeutic capability of genetically modified NSCs rather than naïve NSCs in neurological disease beyond brain tumors and sheds light on the recent progress and prospect in this context.     

TAR RNA结合蛋白在HIV-1感染中的作用

TARRNA结合蛋白是细胞中双链RNA结合蛋白家族成员之一.它可以结合HIV-1TARRNA,并与Tat协同作用激活LTR表达,进而促进病毒的转录与翻译.TRBP也是将干扰素抗病毒通路与RNA干扰免疫通路相连的一种细胞蛋白.在干扰素诱生的PKR反应中,TRBP通过直接抑制PKR的自磷酸化、与PKR竞争通用的RNA底物或与PACT形成异源二聚体等机制抑制细胞内的PKR反应,从而降低了PKR介导的对病毒表达的抑制作用.TRBP与Dicer和Ago2等组成的RNA诱导沉默复合体,在RNA干扰中发挥着关键作用并调控随后的序列特异性降解.在HIV-1感染中,TRBP更倾向于促进病毒的表达与复制,因此TRBP也成为控制HIV-1感染的新靶点.     

The neuroprotective effect of Activin A and B: implication for neurodegenerative diseases

Activin is a member of the transforming growth factor-beta superfamily which comprises a growing list of multifunctional proteins that function as modulators of cell proliferation, differentiation, hormone secretion and neuronal survival. This study examined the neuroprotective effect of both Activin A and B in serum withdrawal and oxidative stress apoptotic cellular models and investigated the expression of pro- and anti-apoptotic proteins, which may account for the mechanism of Activin-induced neuroprotection. Here, we report that recombinant Activin A and B are neuroprotective against serum deprivation- and toxin- [either the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA) or the peroxynitrite donor, 3-(4-morpholinyl) sydnonimine hydrochloride (SIN-1)] induced neuronal death in human SH-SY5Y neuroblastoma cells. Furthermore, we demonstrate for the first time that transient transfection with Activin betaA or betaB significantly protect SH-SY5Y and rat pheochromocytoma PC12 cells against serum withdrawal-induced apoptosis. This survival effect is mediated by the Bcl-2 family members and involves inhibition of caspase-3 activation; reduction of cleaved poly-ADP ribose polymerase and phosphorylated H2A.X protein levels and elevation of tyrosine hydroxylase expression. These results indicate that both Activin-A and -B share the potential to induce neuroprotective activity and thus may have positive impact on aging and neurodegenerative diseases to retard the accelerated rate of neuronal degeneration.     

Lead, copper, zinc, and magnesium content in hair of children and young people with some neurological diseases

The lead, copper, zinc, and magnesium levels of scalp hair taken from 153 children aged 1–15 yr and young people (16–18 yr) with selected neurological disorders (hyperexcibility, loss of consciousness, and epileptiform convulsions of an unknown origin, etc.), were measured using the atomic absorption spectrometry method and then compared with a control group of healthy children (n=108). The research indicated significantly reduced mean levels of magnesium in the hair of children suffering from selected neurological diseases (in children aged 11–15 yr of age, above 30%; up to 5 yr of age, nearly 30%; the differences were statistically significant at p<0.05) and slightly decreased mean levels of copper (differences statistically significant at p<0.05, particularly in the 11 to 15-yr category). Differences in zinc levels in hair were inconsiderable (not statistically significant in any age groups). The lead level in the hair of the above-mentioned group of children was exceeded in relation to the control group (a statistically significant difference at p<0.05 for the total group). A more than twofold decrease in the mean value of the Mg/Pb ratio (and a nearly 30% decrease in the value of the Mg/Zn ratio) in the hair of children suffering from neurological diseases suggests that the high toxicity of lead accompanying, among other things, magnesium deficiencies might be a cause of the observed disorders in children.