CN100448481C - xCT蛋白及其编码基因的新用途 - Google Patents
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Abstract
本发明公开了xCT蛋白及其编码基因在神经变性病发生中的新用途。该xCT蛋白及其编码基因的新用途是首次发现了xCT蛋白及其编码基因在神经变性病中的发生机制，即发现了一种可以导致神经变性病的新的基因。这项发明的意义在于，可以Slc7a11基因或xCT为靶标，筛选可提高Slc7a11基因或xCT的表达量的药物，以提高Slc7a11基因(正常基因)或xCT(正常蛋白)的表达量，增加神经细胞的抗氧化损伤能力，用于预防或减缓神经变性病的发生。对于Slc7a11基因或xCT的表达量低的神经变性病，可利用该神经变性病的动物模型筛选可提高Slc7a11基因或xCT的表达量的蛋白质、核酸、有机小分子等，作为治疗神经变性病的候选药物。
Description
技术领域
本发明涉及xCT蛋白及其编码基因在神经变性病中的新用途。
背景技术
小鼠xCT是由Slc7a11基因编码的502个氨基酸组成的具有12个跨膜结构域的转运蛋白，该基因首次由日本的Sato等(Sato H，Tamba M，Ishii T，et al.Cloning and expression of a plasma membrane cystine/glutamate exchangetransporter composed of two distinct proteins.J Biol Chem.1999；274：11455-11458)于1999年克隆鉴定(GenBank号：AB022345或GI：4689080；提交日期：13-JAN-1999)。同时发现xCT的C158残基通过形成二硫键与另一亚基4Fhc相结合，形成蛋白二聚体，共同组成Xc-氨基酸(胱氨酸/谷氨酸)转运系统，专司胱氨酸从胞外向胞内的运送，同时将谷氨酸转运出细胞外，以1∶1进行交换。
Sut小鼠起源于野生型C3H/HeSnJ的自发突变，已经证实基因组水平只是Slc7a11基因的改变(Swank RT，Reddington M，Novak EK.Inherited prolongedbleeding time and platelet storage pool deficiency in the subtle gray(sut)mouse.Lab Anim Sci.1996；46：56-60)。2005年，Chintala和Li[李巍]等利用定位候选克隆方法发现，因编码xCT蛋白的Slc7a11基因的突变，是subtle gray(sut)(纯合性sut/sut小鼠)小鼠的发病原因，subtle gray(sut)小鼠与野生型C3H/HeSnJ(简写C3H)小鼠相比，只有Slc7a11基因发生突变，其它基因均正常，结果发表在2005年8月份的美国科学院院刊上(Chintala S，Li W，LamoreuxML，et al.Slc7a11 controls the production of pheomelanin pigment and theproliferation of cultured cells.Proc Natl Acad Sci USA，2005；102：10964-10969)。同时李巍等在小鼠脑组织中克隆得到了一条长达9kb以上的cDNA(GenBank登录号：AY766236或GI：59893993；提交日期：29-SEP-2004；提交者：Li，W.[李巍]and Swank，R.T.)。Chintala和Li[李巍]等的研究发现(ChintalaS，Li W，Lamoreux ML，et al.Slc7a11 controls the production of pheomelaninpigment and the proliferation of cultured cells.Proc Natl Acad Sci USA，2005；102：10964-10969)，在体外培养细胞中，由于有充足的O2供应，培养基中所含有的半胱氨酸基本被氧化为胱氨酸。在xCT缺乏的sut小鼠培养的皮肤成纤维细胞和黑色素细胞不能有效利用培养基中的胱氨酸，导致细胞内GSH减少和细胞存活度明显下降。同时，这种对细胞存活的影响，通过在培养液中添加一定浓度的还原剂如β-巯基乙醇(BME)可使细胞生长基本恢复正常。进一步说明xCT蛋白可能通过调节细胞内半胱氨酸的浓度，影响细胞内谷胱甘肽的合成，参与细胞的抗氧化损伤作用。但是其确切的引起细胞死亡的机制尚未阐明。
神经变性病是一大类严重危害人类健康的脑疑难疾病，其中以老年性痴呆(Alzheimer’s disease，AD)和帕金森病(Parkinson’s disease，PD)最为常见，具有高发病率、高患病率和高致残率的特点。随着人口老龄化，我国AD或PD的发病率逐年增高，给家庭和整个社会都带来了沉重的负担。
帕金森病(PD)是一种神经系统退行性疾病，严重影响到患者的健康和生存能力，主要表现为黑质多巴胺能神经元的丧失，纹状体多巴胺含量严重下降，临床上以震颤、强直、运动迟缓为主要表现。至今尚无有效的药物能阻止神经元的变性，使病情逆转。
发明内容
本发明的目的是提供xCT蛋白及其编码基因的新用途。
本发明首次证实Slc7a11基因的突变可以导致神经元变性，证明了Slc7a11基因是与神经变性病相关的基因。
本发明所提供的xCT蛋白及其编码基因(Slc7a11基因)的新用途是xCT蛋白及其编码基因在筛选预防和/或治疗神经变性病药物中的应用。
所述神经变性病包括帕金森氏病和老年性痴呆等。
在实际应用中，可以Slc7a11基因(正常基因)或xCT(正常蛋白)为靶标，筛选可提高Slc7a11基因(正常基因)或xCT(正常蛋白)的表达量的药物，以提高Slc7a11基因(正常基因)或xCT(正常蛋白)的表达量，增加神经细胞的抗氧化损伤能力，从而预防或减缓神经变性病的发生。
对于Slc7a11基因(正常基因)或xCT(正常蛋白)的表达量低的神经变性病，可利用该神经变性病的动物模型筛选可提高Slc7a11基因(正常基因)或xCT(正常蛋白)的表达量的蛋白质、核酸、有机小分子等，作为治疗神经变性病的候选药物。
附图说明
图1为纯合性sut/sut小鼠和C3H/HeSnJ小鼠SHIRPA行为测试结果
图2为纯合性sut/sut小鼠脑的TH免疫组化染色和Calbindin免疫组化染色照片。
图3为纯合性sut/sut小鼠黑色素细胞在缺乏BME时发生的细胞凋亡照片
图4为流式细胞术检测不加BME的纯合性sut/sut小鼠黑色素细胞的凋亡率结果
图5为Western-Blot检测纯合性sut/sut小鼠黑色素细胞的caspase-3，caspase-9被活化和剪切、JNK被磷酸化情况
具体实施方式
下述实验方法如无特别说明，均为常规方法。
实施例1.Slc7a11基因是与神经变性病相关的基因
对9-14周龄的subtle gray(sut/sut)小鼠(购自美国The JacksonLaboratory)和C3H/HeSnJ小鼠(购自美国The Jackson Laboratory)进行了SHIRPA(“一种综合表型评估体系”，详见网址：http://www.mgu.har.mrc.ac.uk/facilities/mutagenesis/mutabase/shirpa_summary.html)行为测试，结果表明，第一批筛选实验(primary screen)中的有10个实验，结果中两组出现差异，表明sut小鼠表现出明显的中枢性共济失调样运动障碍(图1，C3H表示C3H/HeSnJ小鼠)。提示在sut小鼠(sut/sut)中，那些对xCT摄取胱氨酸的依赖性大，用以抵抗氧化应激损伤的运动神经细胞，因xCT缺乏后表现为存活障碍，引起神经变性样改变，导致相应的症状。
对野生型C3H/HeSnJ小鼠、杂合性sut/+小鼠(将野生型C3H/HeSnJ小鼠和纯合性sut/sut小鼠杂交得到的F1代小鼠)和纯合性sut/sut小鼠(购自美国TheJackson Laboratory)脑组织进行酪氨酸羟化酶(TH)免疫组化染色和钙结合蛋白calbindin免疫组化染色，结果如图2所示，表明sut小鼠与运动功能有关的黑质(图2中左侧图片)中的TH染色阳性多巴胺能神经元和与运动功能有关的小脑(图2中右侧图片)中Calbindin染色阳性的Purkinje细胞数目明显减少。说明在sut小鼠中，xCT的缺乏导致了神经细胞的死亡。图2中，最上面的两张图片为野生型C3H/HeSnJ小鼠；中间的两张图片为杂合性sut/+小鼠；下面的两张图片为纯合性sut/sut小鼠。
为了弄清楚xCT缺乏导致神经细胞死亡的确切机制，纯合性sut/sut小鼠黑色素细胞(从英国伦敦St.George医院M.Lynn Lamoreux实验室获得)分别在添加β-巯基乙醇(+BME)，使其终浓度为100μmol/L或不加β-巯基乙醇(-BME)的RPMI1640培养基(美国GIBCO公司产品)中分别培养72和96小时后，用Hoechst33342和PI(propidium iodide)双荧光染色观察细胞核，结果如图3(Hoechst33342染色为蓝色，PI染色为红色)所示，表明随着培养时间的增加，细胞凋亡发生率增加。
纯合性sut/sut小鼠黑色素细胞分别在添加β-巯基乙醇(终浓度为100μmol/L)或不加β-巯基乙醇的RPMI1640培养基中分别培养60、72和96小时后，培养细胞经0.25％胰蛋白酶消化处理后，用70％乙醇固定，PI(propidiumiodide)染色后，在美国BD公司的FACSCalibur流式细胞仪上进行测定，得到与图3相似的结果，即随着培养时间的增加，不加BME的sut黑色素细胞的PI染色阳性细胞凋亡发生率相应增加，在96h时超过10％，对照组为加BME培养96h，凋亡率为1.71％(图4)。图4中，百分数表示凋亡率。
将培养24小时、48小时和72小时的纯合性sut/sut小鼠黑色素细胞，分别设立加BME(终浓度为100μmol/L)或不加BME两组，另外用来源于野生型C57BL/6J小鼠的mela a黑色素细胞系(从英国伦敦St.George医院M.Lynn Lamoreux实验室获得)培养72小时加BME(终浓度为100μmol/L)为对照，收集细胞蛋白后，按常规方法(电泳、转膜、杂交、显色等)进行蛋白质Western印迹实验，所用的剪切caspase-3抗体，caspase-9抗体(caspase-3抗体只检测其剪切体，caspase-9抗体可检测出未剪切和剪切体两种)和磷酸化JNK抗体均购自美国CellSignal公司，所用的上样对照的actin抗体为美国Sigma公司产品。结果检测到培养48到72小时的不加BME的纯合性sut/sut小鼠黑色素细胞中，反映细胞凋亡发生的生化指标如caspase-3，caspase-9被活化和剪切，72小时较48小时更明显，表明xCT缺乏后引起的细胞凋亡是通过caspase-9和caspase-3的通路而引发。同时在培养48到72小时的不加BME的纯合性sut/sut小鼠黑色素细胞中，检测到磷酸化JNK(p-JNK)，同样，72小时较48小时更明显，表明caspase-9和caspase-3上游的JNK信号转导途径被激活(图5)。这些体外实验的结果说明了xCT缺乏细胞的死亡是由于细胞凋亡所引起，并明确了发生细胞凋亡的通路。图5中，“+”表示加β-巯基乙醇，“-”表示未加β-巯基乙醇。
Claims (4)
1、xCT蛋白及其编码基因在筛选预防神经变性病的药物中的应用；所述xCT蛋白的GenBank号是AB022345。
2、根据权利要求1所述的应用，其特征在于：所述神经变性病包括帕金森氏病和老年性痴呆。
3、xCT蛋白及其编码基因筛选治疗神经变性病的药物中的应用；所述xCT蛋白的GenBank号是AB022345。
4、根据权利要求3所述的应用，其特征在于：所述神经变性病包括帕金森氏病和老年性痴呆。
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| CN100448481C true CN100448481C (zh) | 2009-01-07 |
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| WO2017106806A1 (en) * | 2015-12-18 | 2017-06-22 | Federica Cavallo | COMPOSITIONS AND METHODS RELATED TO xCT PEPTIDES |
| CN106526034A (zh) * | 2016-11-18 | 2017-03-22 | 中国医科大学 | 可实现xCT蛋白鉴定及绝对定量的试剂盒及测定方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1556815A (zh) * | 2000-08-04 | 2004-12-22 | �����ִ��ѧҽѧ���� | 用作神经变性疾病诊断的铁调节蛋白-2 |
| CN1617736A (zh) * | 2001-12-06 | 2005-05-18 | 耶达研究及发展有限公司 | 治疗运动神经元疾病的疫苗和方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1556815A (zh) * | 2000-08-04 | 2004-12-22 | �����ִ��ѧҽѧ���� | 用作神经变性疾病诊断的铁调节蛋白-2 |
| CN1617736A (zh) * | 2001-12-06 | 2005-05-18 | 耶达研究及发展有限公司 | 治疗运动神经元疾病的疫苗和方法 |
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