CN1034576C - 淀粉状蛋白空斑核心多肽前体蛋白相关药盒 - Google Patents

淀粉状蛋白空斑核心多肽前体蛋白相关药盒 Download PDF

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CN1034576C
CN1034576C CN88100542A CN88100542A CN1034576C CN 1034576 C CN1034576 C CN 1034576C CN 88100542 A CN88100542 A CN 88100542A CN 88100542 A CN88100542 A CN 88100542A CN 1034576 C CN1034576 C CN 1034576C
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贝诺·梅勒-希尔
康洁
汉斯-格奥尔格·兰玛尔
阿克塞尔·翁塔贝克
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Abstract

本发明涉及淀粉状蛋白空斑核心(APC，Amyloid plaque core)多肽的前体蛋白、该前体蛋白的片段以及该前体蛋白和片段的诊断应用。此外，本发明还涉及编码前体蛋白的DNA、该DNA的片段以及该DNA及其片段的诊断应用。

Description

淀粉状蛋白空斑核心多肽前体蛋白相关药盒
本发明涉及淀粉状蛋白空斑核心〔amyloid plaque core(APC)〕多肽的前体蛋白、该前体蛋白的片段以及该前体蛋白和其片段的诊断应用。此外，本发明还涉及编码该前体蛋白的DNA、该DNA的片段以及该DNA和片段的诊断应用。
早老性痴呆作为一个独立的临床和病理学实体，在1907年由德国神经病学家阿尔茨海默(Alois Alzheimer)第一次予以介绍(Alzheimer，A.(1907)Zentralblatt fr Nervenheilkunde und Psychiabie，177～179)。这种病是老年人最常见的脑病变。现在，仅在美国就有约二百万人患有这种疾病，每年至少有十万人死于此症(Wurtman，R.J.(1985)Sci.Am.252，48～56)。
这种疾病出现在40～80岁的人中间，这些患者渐渐失去他们的记忆和专心致志的能力。在3～10年内，智力衰退的状况恶化到使患者既不能说话、思维，也不能照料自己，以至死亡。造成这种痴呆的病因至今不详，所以既不能确诊，也无法治疗。
对由于患早老性痴呆的死者用显微镜进行大脑尸检，结果揭示了典型的变化。
发现死者大脑尤其在顶骨叶中，即在记忆功能定位的大脑部分，神经元的数量减少。正常释放乙酰胆碱的神经元的失去也明显可见。此外，在大脑皮层中出现三种极端不寻常的结构，这些结构在健康人的大脑中并不存在，因此可以用作(死后)诊断：
1.胞内神经原纤维(NFTs，神经原纤维丛)
在大脑皮层和海马的神经元细胞质体中，发现由两条按螺旋方式相互扭卷的丝构成的丝束(PHFs，成对螺旋丝)。
2.胞外淀粉状蛋白空斑(APC，淀粉状蛋白空斑核心)
轴突空斑含有淀粉状蛋白和死细胞残余物，散布在大脑皮层、海马和扁桃状核上。空斑的数量与智力衰退的程度相关。
3.脑血管淀粉状蛋白(ACA，淀粉状蛋白刚果血管病)
淀粉状蛋白是对一种富含蛋白质的组合物所给出的名称。发现这种无定形蛋白凝集体都围绕着血管且是在大脑血管的管壁内。
ACA的蛋白质组分已经分离得到并已测定了顺序(Glenner，G.G.&Wong，C.W.(1984)Biochem.Biophys.Res.Commun.120，885～890)。该氨基酸顺序与已知蛋白质顺序没有任何同源性。PHF和APC的蛋质组份也已分离得到并已测定了顺序(Masters，C.L，Multhaupt，G.，Simms，G.，Pottgiesser，J.，Martins，R.N.and Beyreuther，K.(1985)EMBO4，2757～2763；Masters，C.L.，Simms，G.，Weinman，N.A.，Multhaupt，G.，McDonald，B.L.and Beyreuther，K.(1985)Proc.Natl.Acad.Sci.USA82，4245～4249)。该氨基酸顺序表明，三个多肽可能是同一个多肽，均具有分子量4.5KD。有关顺序示于图1a-c的方框内(597～638位)。
对于该APC蛋白来源的解释现有几种假说：在大脑内(甚至在另一个器官内)可能是正常蛋白，其中或生物合成的调节受到干扰，或生理降解受到妨碍。大量的积累可能引起疾病。假如是异常蛋白，其不寻常的凝集能力引起了疾病，那么也可能是由于某些因素，例如病毒、食物或环境毒素，在错误控制下由健康人的基因编码的。错误还可能包括原始蛋白质前体的修饰。然而，从另一方面来说，病毒基因也可能是合成APC蛋白的原因。
在导致本发明的工作中，试图确定APC蛋白的来源和性质，以便借此改进诊断早老性痴呆的方法，因为APC蛋白在大脑皮层中的凝集是早老性痴呆患者的主要生物化学标志之一。
为此，构建了含有大脑皮层pA+mRNA的人体胎儿大脑cDNA库。
cDNA采用Okayama和Berg方法(Okayama，H.and Berg，P.Mol.Cell.Biol.2，161-170(1982)；Okayama，H.and Berg，P.Mol.Cell.Biol.3，280～289(1983)合成，并将cDNA转化到大肠杆菌HB101(Aviv，H.and Leder，P.Proc.Natl.Acad.Sci.USA69，1408(1972))中。按这种方法得到的每个cDNA库均含有多于1×106个独立的cDNA克隆。
使用DNA探针筛选cDNA库，探针的顺序由APC多肽的顺序得到。所选择的顺序相当于APC10-16位的氨基酸。有关顺序示于图ic(1815～1835位)。为了确保最佳杂交，考虑了遗传密码的简并性，制备了具有下列顺序的混合物并将其用作探针：这是一个64重简并20聚体。用由人体胎儿大脑皮层库中的100,000个cDNA克隆进行试验，分离得到完全的(全长)cDNA克隆，序号为EC9110，它编码含有APC顺序的蛋白质，因此它是APC肽的前体蛋白。cDNA顺序和编码蛋白的氨基酸顺序示于图(1)。顺序分析采用双脱氧方法进行(Sanger，F.，Nicklen，S.andCoulson，A.R.Proc.Natl.Acad.Sci.USA74，5463～5467(1977)和Guiidelines for quick and simple Plasmid Sequencing，Handbook，(1986)Boehringer Mannheim GmbH，Biochemica，D-6800Mannheim)。关于APC前体蛋白的天然功能，目前一无所知。
因此，本发明涉及图1所示顺序的脱氧核糖核酸及其功能等同物。本文所述“功能等同物”意指：由于遗传密码的简并性，顺序中的各个核苷酸可以交换或衍生化而不影响核酸功能。本发明尤其涉及示于图1中1位至2089位顺序的DNA及其功能等同物。这部分DNA是编码前体蛋白的部分。由于顺序中的某些特殊性，该蛋白质和相应的DNA顺序是在分子水平上诊断早老性痴呆的有意义的工具。在这里，大约从600位至900位的区域尤其值得一提。这部分所编码的酸性氨基酸的数目相对于这部分的长度而言显得特别多。还值得特别注意的是7个连续苏氨酸(位置：DNA819～840/氨基酸274～280)。这些区域由于具有特殊的顺序而很独特，因此可以进行高度专一性的检测，所以对研制诊断用的DNA探针特别有意义。本发明还涉及图1的DNA片段和由该DNA衍生的寡核苷酸及其作为诊断探针的应用。杂交试验时并未用全长的DNA，通常用10至50个左右的核苷酸片段，片段较长常会带来操作上的问题，少于10个核苷酸的片段往往不具有足够的专一性或结合太弱。
图1所示的DNA及其片段可十分满意地用于诊断早老性痴呆，以及检测如缺失、插入和点突变或重排错误之类的突变。
本发明有可能在分子水平上诊断早老性痴呆，同样还可应用于早老性痴呆症状发生前的诊断。也可用DNA工程的已知技术，例如Antonarkais等人介绍的技术(Hum.Gen.69，1～14，1985)进行分析。
本发明还包括由DNA编码的前体蛋白及其片段。该蛋白或其片段的检测同样也是早老性痴呆的诊断手段。该顺序的特殊性(氨基酸：约在200位至290位)也特别重要。前体蛋白的片段，尤其是200至290区，可十分满意地用作制备多克隆或单克隆抗体的抗原肽，而这类抗体同样也可用于诊断。
本文所述蛋白质或肽的功能等同物意指在蛋白质和肽的顺序中，有可能有不影响这些肽的功能(如作为抗原)的氨基酸的交换或衍生形式的变异。
图1a-c的说明：
编码APC多肽前体蛋白的cDNA克隆的核苷酸顺序5′→3′和由该DNA得到的氨基酸顺序。氨基酸的名称用下列单字母代码表示：
氨基酸：
A  Ala    丙氨酸      M  Met    蛋氨酸
B  Asx    天冬酰胺    N  Asn    天冬酰胺
        或天冬氨酸
C  CVs    半胱氨酸    Nle       正亮氨酸
         (胱氨酸)
D  Asp    天冬氨酸    P  Pro    脯氨酸
E  Glu    谷氨酸      Q  Gln    谷氨酰胺
F  Phe    苯丙氨酸    R  Arg    精氨酸
G  GlV    甘氨酸      S  Ser    丝氨酸
H  His    组氨酸      T  hr     苏氨酸
HS        高丝氨酸    V  Val    缬氨酸
HSL       高丝氨酸内酯W  Trp    色氨酸
I  Ile    异亮氨酸    Y  Tyr    酪氨酸
K  LVs    赖氨酸      Z  Glx    谷氨酸或
                                谷氨酰胺
L  Leu    亮氨酸      X  未鉴定

Claims (11)

1.一种检验药盒，该药盒含有图1a-c所示顺序的脱氧核糖核酸及其功能等同物。
2.一种检验药盒，该药盒含有图1a-c所示1位至2089位顺序的脱氧核糖核酸及其功能等同物。
3.一种检验药盒，该药盒合有图1a-c中600位至900位顺序的脱氧核糖核酸及其功能等同物。
4.一种检验药盒，该药盒含有如权利要求1至3所述的脱氧核糖核酸的片段。
5.根据权利要求1至4所述的检验药盒在诊断早老性痴呆中的应用。
6.一种检验药盒，该药盒含有针对图1a-c所示顺序的淀粉状空斑蛋白的前体蛋白及其功能等同物的抗体。
7.一种检验药盒，该药盒含有针对图1a-c所示210位至290位顺序的蛋白质及其功能等同物的抗体。
8.一种检验药盒，该药盒含有针对如权利要求6和7所述蛋白质片段的抗体。
9.根据权利要求6至8所述的检验药盒在诊断早老性痴呆中的应用。
10.一种检验药盒，该药盒含有由图1a-c所示顺序的脱氧核糖核酸得到的寡核苷酸探针。
11.根据权利要求10所述的检验药盒在诊断早老性痴呆中的应用。
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HUT46356A (en) 1988-10-28
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