酵母双杂交筛选帕金森病相关基因LRRK2互作蛋白以及LRRK2和UCH-L1基因启动子区与帕金森病的关联研究
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摘要
帕金森病(Parkinson's disease,PD)是发病率仅次于老年痴呆症的一种进行性神经系统退行性疾病。它多发于中老年人,在50岁以上的人群中发病率约1%。还有一小部分患者,在儿童期或青春期即发病。PD的主要临床症状表现为静止性震颤、肌肉强直、运动迟缓和姿势不稳。除此以外,PD患者还存在一些其他的特殊症状,包括姿势异常、自主神经机能异常、肌张力障碍和痴呆。PD的主要病理改变为大脑黑质多巴胺能神经元的减少,以及包括黑质、蓝斑、基底核、下丘脑和大脑皮层在内的大脑多个区域神经元内出现嗜酸性包涵体—Lewy小体。但常染色体隐性遗传的青少年型PD(Autosomal Recessive Juvenile Parkinson's disease,AR-JP)除外,这种类型的PD患者中不形成Lewy小体。虽然绝大多数PD患者属于散发,遗传因素在PD发病机制中的作用也不可忽视。相关分子遗传学研究已经定位了12个位点与PD相关,并在其中的8个位点上找到了相关基因,包括与常染色体显性遗传PD相关的α-SYNUCLEIN、LRRK2和UCH-L1,以及与常染色体隐性遗传PD相关的PARKIN、PINK1、DJ-1、ATP13A2和HTRA2.
LRRK2基因突变是迄今所有遗传因素中与常染色显性遗传PD和原发性PD联系最紧密的。在散发PD患者中,该基因突变的携带者也达到了史无前例的0.5-3%。LRRK2基因是目前为止与PD发病机制联系最密切的因子。UCH-L1基因是泛素羧基末端水解酶家族的一员,能够从泛素化蛋白中水解出泛素单体,并与其结合,在泛素系统中调节泛素单体的浓度。它特异性的表达于神经系统和生殖系统,通过泛素通路参与包括染色质结构的维持、转录激活、核糖体组装、抗原提呈、蛋白迁移、内涵体-溶酶体形成、细胞周期以及细胞凋亡的调控、DNA修复、精子发生和病毒基因表达的调节等在内的各种细胞学机制。在Lewy小体中发现了UCH-L1蛋白的存在,再考虑到它在蛋白酶体通路中的重要作用,UCH-L1基因很可能在PD的发病机制中发挥重要作用。因此,阐明该基因突变引起神经退行性变的致病机制对于了解并最终战胜PD具有特殊重要的意义。
本研究包括两部分：第一部分是综合生物信息学信息选择LRRK2蛋白的结构域,应用酵母双杂交技术筛选在人胎脑文库中与之互作的蛋白,并通过回交进行初步验证；在第二部分中,在已经定位的LRRK2基因和UCH-L1基因的核心启动子区,设计引物对该区域及其附近的启动子序列进行测序,在PD患者和正常人对照中进行突变检测。
研究发现：1.LRRK2蛋白可能的互作蛋白：以LRRK2蛋白的COR结构域及其两侧序列为诱饵,应用酵母双杂交技术在人胎脑文库中筛选到6个不同的阳性克隆,它们包含的序列在以下几个基因的开放阅读框中：STRBP、BAG、PTPN23、L3MBTL3、KIAA1783; 2.LRRK2基因启动子区突变筛查结果：在108例散发PD患者和197例正常人对照中的LRRK基因启动子区检测到4个SNP位点-838 g/a、-523 a/g、-275 t/c和-221 g／c,所有变异均以杂合的形式存在,未检测到纯合突变。统计学分析不能排除它们与PD的联系；此外,在PD患者中-551a/g和-469g／t变异各检出1例携带者。在正常人中检出1例-696c／t变异携带者。3.UCH-L1基因启动子区突变筛查结果：在118例散发PD患者和246例正常人对照中的UCH-L1基因启动子区检测到5个SNP位点-892 t／c、-307 g/a、-24 g/a、-16 t/c和+247g／c。统计学分析表明,后面4个SNP位点可能位于同一个单体型中影响PD的发生、发病年龄以及其他临床症状的出现；此外,分别在PD患者和正常人中检出-306 g/a.-232a/g、-150 t/c和-974c／t、-957 c/t、-615 t/g、-165 g/c、+52 t/g各1例。
Parkinson's disease (PD) is the second most common neurogenic disorder after Alzheimer disease (AD). The disease is progressive and mostly occurs during middle or old age, affecting approximately 1% of the population over age 50. In very rare cases, symptoms are developed at young age. The primary symptoms of PD includes resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. Pathologic features of classic PD include by a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of eosinophilic intracytoplasmic inclusions known as Lewy bodies, in surviving neurons in various areas of the brain,including substantia nigra, locus ceruleus, nucleus basalis, hypothalamus, and cerebral cortex. Autosomal recessive juvenile Parkinson's disease, however, does not have Lewy body pathology. Although the vast majority of PD cases are thought to be sporadic, the role of genetic factors in PD has been valued more and more. Recent progress in molecular genetics studies of families with PD has led to the identification of 12 loci that are linked to certain inherited forms of PD. These includeα-SYNUCLEIN (PARK1), UCH-L1 (PARK5) and LRRK2 (PARK8) leading to autosomal dominant PD, as well as PARKIN (PARK2), PINK1(PARK6), DJ-1 (PARK7), HTRA2(?ARK12) and ATP13A2(PARK9) leading to early onset recessive PD.
Mutations in LRRK2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic PD. Its mutations are found in approximately 2-13% of patients with familial PD. Importantly, mutations have also been associated with sporadic PD with unprecedented 0.5-3% prevalence. LRRK2 has emerged as, perhaps, the most relevant player in PD pathogenesis identified to date. UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCH-L1 is highly specific to neurons and testis/ovary. Besides its hydrolase activity, UCH-L1 can also associate with monoubiquitin to control ubiquitin levels in the ubiquitin pathway, which has been functionally implicated in various cellular mechanisms, including maintenance of chromatin structurre, transcriptional activation, ribosomal assembly, antigen processing, protein translocation, endosome-lysosome biogenesis, control of the cell cycle and programmed cell death, DNA repair, spermatogenesis, and regulation of viral gene expression et al. Its occurrence in Lewy bodies and its function in the proteasome pathway make it a compelling candidate gene in Parkinson's disease. Therefore, study of LRRK2 and UCH-L1 pathogenic mechanisms relating to neurodegeneration is of crucial importance in understanding and combating PD.
The work includes two parts:In part1, we isolated parts of LRRK2 protein and performed a yeast two-hybrid analysis to isolate and identify its potential binding partners in the human fetal brain cDNA library; In part 2, we sequenced the identified minimum promoter region of LRRK2 gene and UCH-L1 gene in PD patients and unrelated control samples to screen for mutations related with PD.
Our results show that:1.Potential binding partners of LRRK2 in the human fetal brain cDNA library:Employing a sequence containing full-length of COR domain and part of ROC and MAPKKK domain as bait, we identified STRBP、BAG5、PTPN23、L3MBTL3、RALYL and KIAA1783 as potential binding partners of LRRK2 in the human fetal brain cDNA library through yeast two-hybrid screens; 2.Mutations in the promoter region of LRRK2 gene:In 108 sporadic PD patients and 197 unrelated control samples, we found 4 SNP positions,-838 g/a,-523 a/g,-275 t/c and -221 g/c, in the promoter region of LRRK2 gene and statistical analysis could not completely eliminate the possibility that they are associated with PD. In the region, we also found 2 mutations,-551 a/g and -469 g/t, carried in different PD patients and 1 mutation,-696 c/t,in a healthy control; 3. Mutations in the promoter region of UCH-L1 gene: In 118 sporadic PD patients and 246 unrelated control samples, we found 5 SNP positions,-892 t/c,-307 g/a,-24 g/a,-16 t/c and +247 g/c, in the promoter region of UCH-L1 gene and statistical analysis showed that the last 4 SNP positions may participate in the same haplotype block associated with PD. Besides, we also found-306 g/a,-232 a/g and -150 t/c once in different PD patients and-974 c/t,-957 c/t,-615 t/g,-165 g/c and +52 t/g once in different healthy control.
LRRK2基因突变是迄今所有遗传因素中与常染色显性遗传PD和原发性PD联系最紧密的。在散发PD患者中,该基因突变的携带者也达到了史无前例的0.5-3%。LRRK2基因是目前为止与PD发病机制联系最密切的因子。UCH-L1基因是泛素羧基末端水解酶家族的一员,能够从泛素化蛋白中水解出泛素单体,并与其结合,在泛素系统中调节泛素单体的浓度。它特异性的表达于神经系统和生殖系统,通过泛素通路参与包括染色质结构的维持、转录激活、核糖体组装、抗原提呈、蛋白迁移、内涵体-溶酶体形成、细胞周期以及细胞凋亡的调控、DNA修复、精子发生和病毒基因表达的调节等在内的各种细胞学机制。在Lewy小体中发现了UCH-L1蛋白的存在,再考虑到它在蛋白酶体通路中的重要作用,UCH-L1基因很可能在PD的发病机制中发挥重要作用。因此,阐明该基因突变引起神经退行性变的致病机制对于了解并最终战胜PD具有特殊重要的意义。
本研究包括两部分：第一部分是综合生物信息学信息选择LRRK2蛋白的结构域,应用酵母双杂交技术筛选在人胎脑文库中与之互作的蛋白,并通过回交进行初步验证；在第二部分中,在已经定位的LRRK2基因和UCH-L1基因的核心启动子区,设计引物对该区域及其附近的启动子序列进行测序,在PD患者和正常人对照中进行突变检测。
研究发现：1.LRRK2蛋白可能的互作蛋白：以LRRK2蛋白的COR结构域及其两侧序列为诱饵,应用酵母双杂交技术在人胎脑文库中筛选到6个不同的阳性克隆,它们包含的序列在以下几个基因的开放阅读框中：STRBP、BAG、PTPN23、L3MBTL3、KIAA1783; 2.LRRK2基因启动子区突变筛查结果：在108例散发PD患者和197例正常人对照中的LRRK基因启动子区检测到4个SNP位点-838 g/a、-523 a/g、-275 t/c和-221 g／c,所有变异均以杂合的形式存在,未检测到纯合突变。统计学分析不能排除它们与PD的联系；此外,在PD患者中-551a/g和-469g／t变异各检出1例携带者。在正常人中检出1例-696c／t变异携带者。3.UCH-L1基因启动子区突变筛查结果：在118例散发PD患者和246例正常人对照中的UCH-L1基因启动子区检测到5个SNP位点-892 t／c、-307 g/a、-24 g/a、-16 t/c和+247g／c。统计学分析表明,后面4个SNP位点可能位于同一个单体型中影响PD的发生、发病年龄以及其他临床症状的出现；此外,分别在PD患者和正常人中检出-306 g/a.-232a/g、-150 t/c和-974c／t、-957 c/t、-615 t/g、-165 g/c、+52 t/g各1例。
Parkinson's disease (PD) is the second most common neurogenic disorder after Alzheimer disease (AD). The disease is progressive and mostly occurs during middle or old age, affecting approximately 1% of the population over age 50. In very rare cases, symptoms are developed at young age. The primary symptoms of PD includes resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. Pathologic features of classic PD include by a loss of dopaminergic neurons in the substantia nigra (SN) and the presence of eosinophilic intracytoplasmic inclusions known as Lewy bodies, in surviving neurons in various areas of the brain,including substantia nigra, locus ceruleus, nucleus basalis, hypothalamus, and cerebral cortex. Autosomal recessive juvenile Parkinson's disease, however, does not have Lewy body pathology. Although the vast majority of PD cases are thought to be sporadic, the role of genetic factors in PD has been valued more and more. Recent progress in molecular genetics studies of families with PD has led to the identification of 12 loci that are linked to certain inherited forms of PD. These includeα-SYNUCLEIN (PARK1), UCH-L1 (PARK5) and LRRK2 (PARK8) leading to autosomal dominant PD, as well as PARKIN (PARK2), PINK1(PARK6), DJ-1 (PARK7), HTRA2(?ARK12) and ATP13A2(PARK9) leading to early onset recessive PD.
Mutations in LRRK2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic PD. Its mutations are found in approximately 2-13% of patients with familial PD. Importantly, mutations have also been associated with sporadic PD with unprecedented 0.5-3% prevalence. LRRK2 has emerged as, perhaps, the most relevant player in PD pathogenesis identified to date. UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCH-L1 is highly specific to neurons and testis/ovary. Besides its hydrolase activity, UCH-L1 can also associate with monoubiquitin to control ubiquitin levels in the ubiquitin pathway, which has been functionally implicated in various cellular mechanisms, including maintenance of chromatin structurre, transcriptional activation, ribosomal assembly, antigen processing, protein translocation, endosome-lysosome biogenesis, control of the cell cycle and programmed cell death, DNA repair, spermatogenesis, and regulation of viral gene expression et al. Its occurrence in Lewy bodies and its function in the proteasome pathway make it a compelling candidate gene in Parkinson's disease. Therefore, study of LRRK2 and UCH-L1 pathogenic mechanisms relating to neurodegeneration is of crucial importance in understanding and combating PD.
The work includes two parts:In part1, we isolated parts of LRRK2 protein and performed a yeast two-hybrid analysis to isolate and identify its potential binding partners in the human fetal brain cDNA library; In part 2, we sequenced the identified minimum promoter region of LRRK2 gene and UCH-L1 gene in PD patients and unrelated control samples to screen for mutations related with PD.
Our results show that:1.Potential binding partners of LRRK2 in the human fetal brain cDNA library:Employing a sequence containing full-length of COR domain and part of ROC and MAPKKK domain as bait, we identified STRBP、BAG5、PTPN23、L3MBTL3、RALYL and KIAA1783 as potential binding partners of LRRK2 in the human fetal brain cDNA library through yeast two-hybrid screens; 2.Mutations in the promoter region of LRRK2 gene:In 108 sporadic PD patients and 197 unrelated control samples, we found 4 SNP positions,-838 g/a,-523 a/g,-275 t/c and -221 g/c, in the promoter region of LRRK2 gene and statistical analysis could not completely eliminate the possibility that they are associated with PD. In the region, we also found 2 mutations,-551 a/g and -469 g/t, carried in different PD patients and 1 mutation,-696 c/t,in a healthy control; 3. Mutations in the promoter region of UCH-L1 gene: In 118 sporadic PD patients and 246 unrelated control samples, we found 5 SNP positions,-892 t/c,-307 g/a,-24 g/a,-16 t/c and +247 g/c, in the promoter region of UCH-L1 gene and statistical analysis showed that the last 4 SNP positions may participate in the same haplotype block associated with PD. Besides, we also found-306 g/a,-232 a/g and -150 t/c once in different PD patients and-974 c/t,-957 c/t,-615 t/g,-165 g/c and +52 t/g once in different healthy control.
引文
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