散发性肌萎缩侧索硬化患者GSTT1、M1，CYP1A1基因多态性分析
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摘要
目的:肌萎缩侧索硬化(Amyotrophic Lateral Sclerosis, ALS)是一种成年起病,选择性侵犯运动神经元的神经系统慢性进展性变性疾病。临床表现为缓慢进展的四肢瘫痪,累及呼吸肌,多在3-5年内死亡。大约10%的患者为家族性ALS (familial ALS, fALS), fALS中约20%是由于编码Cu/Zn超氧化物歧化酶(SOD1)的基因突变所致。约90%的患者为散发性ALS (sporadic ALS, sALS),病因及发病机制尚不十分清楚,一般认为是多因素包括遗传因素和环境因素共同作用的结果。sALS患者运动神经元死亡的原因至今仍不清楚,目前推测的发病机制主要有:氧化应激,谷氨酸兴奋毒作用,免疫炎症和凋亡等。这些因素相互作用,相互影响,共同参与了运动神经元的变性和死亡。近年来越来越多的证据表明氧化应激在ALS的发病机制中发挥重要作用,尤其是在疾病的早期,氧化应激促进了神经元的损伤和疾病的进展。另外许多证据表明环境毒素和化学致癌物对神经元具有损害作用,它们通过介导体内产生大量的氧自由基造成神经元的氧化损伤,导致神经元的变性和死亡。机体具有强大的代谢酶防御系统,能够清除自由基,抵抗外界氧化损伤和代谢清除外来有毒化合物,保护机体免受损伤。分子遗传学方面的研究表明,编码这些生物转化酶的基因在人群中存在着广泛的多态性,某些易感基因型能造成其编码的酶蛋白活性下降或丧失,导致机体对某些疾病的易感性增加。本试验目的在于探讨GSTT1、M1基因和CYP1A1基因多态性与散发性肌萎缩侧索硬化遗传易感性之间的关系。
方法:选自我院神经科的散发性ALS患者135例,由运动神经元病专业医师根据世界神经病学会联盟EI Escorial诊断标准进行诊断和鉴别诊断,根据家族史排除家族性ALS。210例无直接血缘关系的河北省健康个体,均来自我院门诊健康体检人员,并符合以下标准:无任何遗传倾向性疾病;在取样当时均未诊断有肿瘤、心脑血管病、精神异常及其他重大健康问题。两组对象间无血缘关系,两组的年龄、性别比、身高、体重均具有可比性。采用内对照多重聚合酶链反应技术(PCR)和凝胶成像分析技术确定GSTT1和GSTM1的基因型。采用聚合酶链技术和限制性片段长度多态性分析技术(PCR-RFLP)确定CYP1A1的基因型。全部数据采用SAS v8进行统计分析。研究数据均以均值±SD(标准差)表示。对照组及病例组的基因型分布及等位基因频率应用基因计数法得出,并通过Χ2检验与Hardy-Weinberg平衡进行验证。计数资料比较采用Χ2检验。采用比值比(OR)评价可能致病因素的影响,并计算其95%的可信区间(95% CI)。
结果:对散发性肌萎缩侧索硬化病例组和对照组中CYP1A1基因型频率进行Hardy-Weinberg平衡检验(Table 2),结果均为P>0.05,表明在所选群体中CYP1A1基因型及其等位基因的分布已达遗传平衡,可进一步进行两组间的Χ2检验。病例组和对照组中GSTT1基因缺失型的频率分别为44.4%和48.6%。两组间基因型分布差异无统计学意义(P=0.4525>0.05)。GSTM1基因缺失型的频率在病例组和对照组中分别为49.6%和30.6%,两组间基因型分布差异亦无统计学意义(P=0.0859>0.05)。GSTT1基因和GSTM1基因联合分析显示:GSTT1/GSTM1中4种联合基因型在病例组和对照组两组人群中的分布频率差异无统计学意义(P=0.2067>0.05)。CYP1A1等位基因t和c在病例组的分布频率为60.7%和39.3%,在对照组为63.8%和36.2%。两组间差异无统计学意义(P=0.4162),OR值为1.14(95%CI为0.83-1.56),CYP1A1基因三种基因型在两组间的分布频率差异无统计学意义(P=0.1034>0.05)。但是经过性别分层分析后发现在男性人群中,CYP1A1三种基因型在病例组和对照组中分布频率差异有统计学意义(P=0.1034),在病例组中C/C基因型比例明显增加。
结论:本试验首次研究了GSTT1,GSTM1和CYP1A1基因多态性与中国散发性肌萎缩侧索硬化的关系。中国人群中GSTT1,GSTM1的缺失多态性可能与sALS的发病无明显相关性;CYP1A1基因MspI多态性很可能与sALS的发病相关,尤其是在男性患者中,其中CYP1A1基因MspI多态性中,C/C基因型增加了男性罹患ALS的风险性。
Objictive: Amyotrophic lateral sclerosis (ALS) is an age- dependent, progressive neurodegenerative disease selectively affecting motoneurons. It is a rapidly progressive disease that results in progressive paralysis until death occurs, usually within 3 to 5 years of onset. Approximately 10% of cases are familial (fALS), of which approximately 20% can be explained by mutations in SOD1. The remaining 90% or more of cases are sporadic ALS (sALS), and are thought to be multifactorial, with both environmental and genetic components. The cause of motor neuron degeneration in sporadic ALS is unknown, but the many possible mechanisms include oxidative stress, glutamate- mediated excitotoxicity, inflammation and apoptosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation of the disease. There is increasing evidence that environmental toxins and carcinogenic com- pounds may damage motor neuron by way of reactive oxygen species(ROS) induced cellular injury. Increased ROS levels may cause oxidative damage within motor neurons. Researches in molecular genetics have revealed that polymorphisms of some metabolizing enzyme genes, causing the enzymes with lower or losing functions of detoxification and antioxidant, may related to the development of sporadic ALS. In this study, we aimed primarily to evaluate whether polymorphisms of genes encoding the metabolic enzymes such as glutathione S-transferaseT1 (GSTT1), M1 (GSTM1) and Cytochrome P450 1A1 (CYP1A1) might contribute to the variability in individual susceptibility to sporadic ALS.
Methods: The study population comprised 135 china patients with sporadic ALS and 210 control subjects. Controls were all healthy subjects matched by age and sex with sALS patients. All patients fulfilled the El Escorial criteria. Cases with familial ALS were excluded. Control subjects had no history of neurological disease and no family history of ALS. All cases and controls were of China ethnicity. The polymorphic deletion of the GSTM1 and GSTT1 genes were genotyped using the multiplex PCR approach described previously, CYP1A1 polymorphism were determined by the Method of Restriction fragment length polymorphism analysis (RFLP). Statistical analysis was done using the Statistical Analysis System (SAS) for Windows (version 8.0). Data are presented as mean±SD. The CYP1A1 genotypes distributions was compared with that as expected from Hardy-Weinberg equilibrium byχ2 tests. The difference in frequency distributions of genotypes and phenol- types between the two groups was tested byχ2 test. The association between GSTT1, GSTM1 and CYP1A1 genotypes and sporadic ALS risk was analyzed by calculating the crude odds ratios (OR) and 95% confidence intervals (95% CI) using theχ2 test.
Results: Hardy-Weinberg analysis was performed to compare the observed and expected genotype frequencies of CYP1A1 usingχ2 tests, finally shows P>0.05, indicated in choosing the community the candidate gene has reached the heredity balance. The frequencies of GSTT1 null genotype in sporadic ALS patients groups and control groups were 44.4% and 48.6% respectively, The percentage of GSTM1 null genotype in cases and controls were 49.6% and 30.6% respectively. There were no significant differences in GSTT1 and GSTM1 genotype frequencies between cases and controls (p=0.4535 and 0.0859 respectively), and no statistically significant associations between the GSTT1/GSTM1 polymor- phisms and sporadic ALS risk (p=0.2067). In the CYP1A1 group, although no significant differences in total t and c allelic frequencies were noted between sporadic ALS patients and controls(P=0.4162, OR=1.14, 95%CI 0.83- 1.56), and analysis of the genotype distribution also failed to detect a significant difference between sporadic ALS and controls (P=0.1034), we found a modest association of C/C genotype of CYP1A1 with increased risk of sALS in our male population (P=0.0108).
Conclusion: This is the first observational study to examine the association between the polymorphisms of The GSTT1, GSTM1 and CYP1A1 and the risk of sporadic ALS. We find that GSTT1, GSTM1 polymorphism does not influence the overall risk of sporadic ALS in Chinese population, CYP1A1 polymorphisms maybe affect incidence rate of sporadic ALS in Chinese male population.
方法:选自我院神经科的散发性ALS患者135例,由运动神经元病专业医师根据世界神经病学会联盟EI Escorial诊断标准进行诊断和鉴别诊断,根据家族史排除家族性ALS。210例无直接血缘关系的河北省健康个体,均来自我院门诊健康体检人员,并符合以下标准:无任何遗传倾向性疾病;在取样当时均未诊断有肿瘤、心脑血管病、精神异常及其他重大健康问题。两组对象间无血缘关系,两组的年龄、性别比、身高、体重均具有可比性。采用内对照多重聚合酶链反应技术(PCR)和凝胶成像分析技术确定GSTT1和GSTM1的基因型。采用聚合酶链技术和限制性片段长度多态性分析技术(PCR-RFLP)确定CYP1A1的基因型。全部数据采用SAS v8进行统计分析。研究数据均以均值±SD(标准差)表示。对照组及病例组的基因型分布及等位基因频率应用基因计数法得出,并通过Χ2检验与Hardy-Weinberg平衡进行验证。计数资料比较采用Χ2检验。采用比值比(OR)评价可能致病因素的影响,并计算其95%的可信区间(95% CI)。
结果:对散发性肌萎缩侧索硬化病例组和对照组中CYP1A1基因型频率进行Hardy-Weinberg平衡检验(Table 2),结果均为P>0.05,表明在所选群体中CYP1A1基因型及其等位基因的分布已达遗传平衡,可进一步进行两组间的Χ2检验。病例组和对照组中GSTT1基因缺失型的频率分别为44.4%和48.6%。两组间基因型分布差异无统计学意义(P=0.4525>0.05)。GSTM1基因缺失型的频率在病例组和对照组中分别为49.6%和30.6%,两组间基因型分布差异亦无统计学意义(P=0.0859>0.05)。GSTT1基因和GSTM1基因联合分析显示:GSTT1/GSTM1中4种联合基因型在病例组和对照组两组人群中的分布频率差异无统计学意义(P=0.2067>0.05)。CYP1A1等位基因t和c在病例组的分布频率为60.7%和39.3%,在对照组为63.8%和36.2%。两组间差异无统计学意义(P=0.4162),OR值为1.14(95%CI为0.83-1.56),CYP1A1基因三种基因型在两组间的分布频率差异无统计学意义(P=0.1034>0.05)。但是经过性别分层分析后发现在男性人群中,CYP1A1三种基因型在病例组和对照组中分布频率差异有统计学意义(P=0.1034),在病例组中C/C基因型比例明显增加。
结论:本试验首次研究了GSTT1,GSTM1和CYP1A1基因多态性与中国散发性肌萎缩侧索硬化的关系。中国人群中GSTT1,GSTM1的缺失多态性可能与sALS的发病无明显相关性;CYP1A1基因MspI多态性很可能与sALS的发病相关,尤其是在男性患者中,其中CYP1A1基因MspI多态性中,C/C基因型增加了男性罹患ALS的风险性。
Objictive: Amyotrophic lateral sclerosis (ALS) is an age- dependent, progressive neurodegenerative disease selectively affecting motoneurons. It is a rapidly progressive disease that results in progressive paralysis until death occurs, usually within 3 to 5 years of onset. Approximately 10% of cases are familial (fALS), of which approximately 20% can be explained by mutations in SOD1. The remaining 90% or more of cases are sporadic ALS (sALS), and are thought to be multifactorial, with both environmental and genetic components. The cause of motor neuron degeneration in sporadic ALS is unknown, but the many possible mechanisms include oxidative stress, glutamate- mediated excitotoxicity, inflammation and apoptosis. Although multiple mechanisms clearly can contribute to the pathogenesis of motor neuron injury, recent advances suggest that oxidative stress may play a significant role in the amplification, and possibly the initiation of the disease. There is increasing evidence that environmental toxins and carcinogenic com- pounds may damage motor neuron by way of reactive oxygen species(ROS) induced cellular injury. Increased ROS levels may cause oxidative damage within motor neurons. Researches in molecular genetics have revealed that polymorphisms of some metabolizing enzyme genes, causing the enzymes with lower or losing functions of detoxification and antioxidant, may related to the development of sporadic ALS. In this study, we aimed primarily to evaluate whether polymorphisms of genes encoding the metabolic enzymes such as glutathione S-transferaseT1 (GSTT1), M1 (GSTM1) and Cytochrome P450 1A1 (CYP1A1) might contribute to the variability in individual susceptibility to sporadic ALS.
Methods: The study population comprised 135 china patients with sporadic ALS and 210 control subjects. Controls were all healthy subjects matched by age and sex with sALS patients. All patients fulfilled the El Escorial criteria. Cases with familial ALS were excluded. Control subjects had no history of neurological disease and no family history of ALS. All cases and controls were of China ethnicity. The polymorphic deletion of the GSTM1 and GSTT1 genes were genotyped using the multiplex PCR approach described previously, CYP1A1 polymorphism were determined by the Method of Restriction fragment length polymorphism analysis (RFLP). Statistical analysis was done using the Statistical Analysis System (SAS) for Windows (version 8.0). Data are presented as mean±SD. The CYP1A1 genotypes distributions was compared with that as expected from Hardy-Weinberg equilibrium byχ2 tests. The difference in frequency distributions of genotypes and phenol- types between the two groups was tested byχ2 test. The association between GSTT1, GSTM1 and CYP1A1 genotypes and sporadic ALS risk was analyzed by calculating the crude odds ratios (OR) and 95% confidence intervals (95% CI) using theχ2 test.
Results: Hardy-Weinberg analysis was performed to compare the observed and expected genotype frequencies of CYP1A1 usingχ2 tests, finally shows P>0.05, indicated in choosing the community the candidate gene has reached the heredity balance. The frequencies of GSTT1 null genotype in sporadic ALS patients groups and control groups were 44.4% and 48.6% respectively, The percentage of GSTM1 null genotype in cases and controls were 49.6% and 30.6% respectively. There were no significant differences in GSTT1 and GSTM1 genotype frequencies between cases and controls (p=0.4535 and 0.0859 respectively), and no statistically significant associations between the GSTT1/GSTM1 polymor- phisms and sporadic ALS risk (p=0.2067). In the CYP1A1 group, although no significant differences in total t and c allelic frequencies were noted between sporadic ALS patients and controls(P=0.4162, OR=1.14, 95%CI 0.83- 1.56), and analysis of the genotype distribution also failed to detect a significant difference between sporadic ALS and controls (P=0.1034), we found a modest association of C/C genotype of CYP1A1 with increased risk of sALS in our male population (P=0.0108).
Conclusion: This is the first observational study to examine the association between the polymorphisms of The GSTT1, GSTM1 and CYP1A1 and the risk of sporadic ALS. We find that GSTT1, GSTM1 polymorphism does not influence the overall risk of sporadic ALS in Chinese population, CYP1A1 polymorphisms maybe affect incidence rate of sporadic ALS in Chinese male population.
引文
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12 Kikuchi S, Shinpo K, Ogata A, et al. Detection of N epsilon- (carboxymethyl)ysine (CML) and non-CML advanced glycation end-products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Amyotrophic Lateral Scler, Other Mot, Neuron Disord, 2002, 3, 63~68
13 Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem, 1997, 69: 2064~2074
14 Barber SC, Mead RJ, Shaw, PJ. Oxidative stress in ALS: A mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta, 2006, 1762: 1051~1067
15 Simpson EP, Yen AA, Appel SH. Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Curr Opin Rheumatol, 2003, 15: 730~736.
16 Beal MF, Ferrante RJ, Browne SE, et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 1997, 42: 644~654
17 Chou SM, Wang HS, Komai K. Colocalization of NOS and SOD1 in neurofilament accumulation within motorneurones of ALS: an immunohistochemical study. J Chem Neuroanat,1996, 10: 249~258
18 Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem, 1997, 69: 2064~2074
19 Shaw PJ, Ince PG, Falkous G, te al. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol, 1995, 38: 691~695
20 Couratier P, Hugon J, Sindou P, et al. Cell culture evidence for neuronal degeneration in anyotrofic lateral sclerosis being linked to glutamate AMPA/kainite receptors. Lancet, 1993, 34: 265~268
21 Pedersen WA, Fu W, Keller JN, et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrofic lateral sclerosis patients. Ann Neurol, 1998, 44: 819~824
22 Bowling AC, Schulz JB, Brown RH, et al. Superoxide dismutaseactivity, oxidative damage and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem, 1993, 64: 2366~2369
23 Aguirre T, Van Den, Bosch L, et al. Increased sensitivity of fibroblasts from ALS patients to oxidative stress. Ann Neurol, 1998, 43: 452~457
24 Simpson EP, Henry YK, Henkel JS, te al. Increased lipid peroxidation in sera of ALS patients: A potential biomarker of disease burden. Neurology 2004, 62: 1758~1765
25 Andrus PK, Fleck TJ, Gurne ME, et al. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem, 1998, 7: 2041~2048
26 Liu R, Althaus JS, Ellerbrock BR, et al. Enhanced oxygen radical production in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ann Neurol, 1998, 44: 763~770
27 Poon HF, Hensley K, Thongboonkerd V, et al. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis, Free Radical Biol Med, 2005, 39: 453~462
28 Casoni F, Basso M, Massignan T, et al. Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis, J Biol Chem, 2005, 280: 16295~16304
29 Robberecht W, Aguirre T, Van Den Bosch L, et al. D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. Neurology, 1996, 47: 1336~1339
30 Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor neurontoxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 1998, 281: 1851~1854
31 Ripps ME, Huntely GW, Hof PR, et al. Transgenic miceexpressing an altered murine superoxide dismutase gene provide an animal model of amyotrofic lateral sclerosis. Proc Natl Acad Sci USA, 1995, 92: 689~693
32 Wim Robberecht MD. Oxidative stress in amyotrophic lateral sclerosis. J Neurol, 2000, 247: I/1~I/6
33 Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging, 2002, 23: 795~807
34 AV Rao, Balachandran B. Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr Neurosci, 2002, 5: 291~309
35 Cole GM. Ironic fate: can a banned drug control metal heavies in neurodegenerative diseases? Neuron, 2003, 37: 889~890
36 Cuajungco MP, Faget KY, Huang X, et al. Metal chelation as a potential therapy for Alzheimer’s disease. Ann NY Acad Sci, 2000, 920: 292~304
37 Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med, 1994, 330: 613~622
38 Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve, 2002, 26: 438~458
39 Spreux-Varoquaux O, Bensimon G, Lacomblez L, et al. Glutamate levels in cerebrospinal fluid in amyotrophiclateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci, 2002, 193: 73~78
40 Bendotti C, Tortarolo M, Suchak SK,et al. Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem, 2001, 79: 737~746
41 Howland DS, Liu J, She Y, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA, 2002, 99: 1604~1609
42 Siklos L, Engelhardt J, Harati Y, et al. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis, Ann Neurol, 1996, 39: 203~216
43 Siklos L, Engelhardt JI, Alexianu ME, et al. Intracellular calcium parallels motoneuron degeneration in SOD-1mutant mice. J Neuropathol Exp Neurol, 1998, 57: 571~587
44 Dykens JA. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: implications for neurodegeneration. J Neurochem, 1994, 63: 584~591
45 Stout AK, Raphael HM, Kanterewicz BI, et al. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci, 1998, 1: 366~373
46 Carriedo SG, Sensi SL, Yin HZ, et al. AMPA exposures induce mitochondrial Ca2+ overload and ROS generation inspinal motor neurons in vitro. J Neurosci, 2000, 20: 240~250
47 Trotti D, Rossi D, Gjesdal O, et al. Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem, 1996, 271: 5976~5979
48 Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidantvulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci, 1998, 19: 328~334
49 Trotti D, Rolfs A, Danbolt NC, et al. SOD1mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci, 1999, 2: 427~433
50 Pedersen WA, Fu W, Keller JN, et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann Neurol, 1998, 44: 819~824
51 Subramaniam JR, Lyons WE, Liu J, et al. Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nat Neurosci, 2002, 5: 301~307
52 Wang J, Slunt H, Gonzales V, et al. Copperbinding-site-null SOD1 causes ALS in transgenic mice: Aggregates of non-native SOD1 delineate a common feature. Hum Mol Genet, 2003, 12: 2753~2764
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1 Figlewicz DA, Orrell RW, The genetics of motor neuron diseases. Amyotroph Lateral Scler. Other Mot. Neuron Disord. 2003, 4: 225~231
2 Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 1993, 362: 59~62
3 Oteiza PI, Uchitel OD, Carrasquedo F, et al. Evaluation of antioxidants, protein,and lipid oxidation products in blood from sporadic amyotrophic lateral sclerosis patients. Neurochem Res 1997, 22: 535~539
4 Halliwell B, Gutteridge JMC, Free Radicals in Biology and Medicine, 3rd ed, Oxford Univ Press, Oxford , 1999
5 Pryor WA, Squadrito GL, The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide, Am J Physiol, 1995, 268: L699~L722
6 Coyle JT, Puttfarcken P. Oxidative stress, glutamate and neurodegenerative disorders. Science, 1993, 262: 689~695
7 Wasserman WW, Fahl WE. Functional antioxidant responsive element. Proc Natl Acad Sci USA, 1997, 94(10): 5361~5366
8 Nguyen T, Sherratt PJ, Pickett CB Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol, 2003, 43: 233~260
9 Lee JM, Johnson JA. An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol, 2004, 37(2): 139~143
10 Skaper SD, Floreani M, Ceccon M,et al. Excitotoxicity,Oxidative Stress, and the Neuroprotective Potential of Melatonin. Ann NY Acad Sci, 1999, 890: 107~118
11 Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci, 2004, 27: 723~749
12 Kikuchi S, Shinpo K, Ogata A, et al. Detection of N epsilon- (carboxymethyl)ysine (CML) and non-CML advanced glycation end-products in the anterior horn of amyotrophic lateral sclerosis spinal cord. Amyotrophic Lateral Scler, Other Mot, Neuron Disord, 2002, 3, 63~68
13 Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem, 1997, 69: 2064~2074
14 Barber SC, Mead RJ, Shaw, PJ. Oxidative stress in ALS: A mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta, 2006, 1762: 1051~1067
15 Simpson EP, Yen AA, Appel SH. Oxidative Stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Curr Opin Rheumatol, 2003, 15: 730~736.
16 Beal MF, Ferrante RJ, Browne SE, et al. Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 1997, 42: 644~654
17 Chou SM, Wang HS, Komai K. Colocalization of NOS and SOD1 in neurofilament accumulation within motorneurones of ALS: an immunohistochemical study. J Chem Neuroanat,1996, 10: 249~258
18 Ferrante RJ, Browne SE, Shinobu LA, et al. Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. J Neurochem, 1997, 69: 2064~2074
19 Shaw PJ, Ince PG, Falkous G, te al. Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann Neurol, 1995, 38: 691~695
20 Couratier P, Hugon J, Sindou P, et al. Cell culture evidence for neuronal degeneration in anyotrofic lateral sclerosis being linked to glutamate AMPA/kainite receptors. Lancet, 1993, 34: 265~268
21 Pedersen WA, Fu W, Keller JN, et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrofic lateral sclerosis patients. Ann Neurol, 1998, 44: 819~824
22 Bowling AC, Schulz JB, Brown RH, et al. Superoxide dismutaseactivity, oxidative damage and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem, 1993, 64: 2366~2369
23 Aguirre T, Van Den, Bosch L, et al. Increased sensitivity of fibroblasts from ALS patients to oxidative stress. Ann Neurol, 1998, 43: 452~457
24 Simpson EP, Henry YK, Henkel JS, te al. Increased lipid peroxidation in sera of ALS patients: A potential biomarker of disease burden. Neurology 2004, 62: 1758~1765
25 Andrus PK, Fleck TJ, Gurne ME, et al. Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem, 1998, 7: 2041~2048
26 Liu R, Althaus JS, Ellerbrock BR, et al. Enhanced oxygen radical production in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ann Neurol, 1998, 44: 763~770
27 Poon HF, Hensley K, Thongboonkerd V, et al. Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice—A model of familial amyotrophic lateral sclerosis, Free Radical Biol Med, 2005, 39: 453~462
28 Casoni F, Basso M, Massignan T, et al. Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis, J Biol Chem, 2005, 280: 16295~16304
29 Robberecht W, Aguirre T, Van Den Bosch L, et al. D90A heterozygosity in the SOD1 gene is associated with familial and apparently sporadic amyotrophic lateral sclerosis. Neurology, 1996, 47: 1336~1339
30 Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor neurontoxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 1998, 281: 1851~1854
31 Ripps ME, Huntely GW, Hof PR, et al. Transgenic miceexpressing an altered murine superoxide dismutase gene provide an animal model of amyotrofic lateral sclerosis. Proc Natl Acad Sci USA, 1995, 92: 689~693
32 Wim Robberecht MD. Oxidative stress in amyotrophic lateral sclerosis. J Neurol, 2000, 247: I/1~I/6
33 Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging, 2002, 23: 795~807
34 AV Rao, Balachandran B. Role of oxidative stress and antioxidants in neurodegenerative diseases. Nutr Neurosci, 2002, 5: 291~309
35 Cole GM. Ironic fate: can a banned drug control metal heavies in neurodegenerative diseases? Neuron, 2003, 37: 889~890
36 Cuajungco MP, Faget KY, Huang X, et al. Metal chelation as a potential therapy for Alzheimer’s disease. Ann NY Acad Sci, 2000, 920: 292~304
37 Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med, 1994, 330: 613~622
38 Heath PR, Shaw PJ. Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. Muscle Nerve, 2002, 26: 438~458
39 Spreux-Varoquaux O, Bensimon G, Lacomblez L, et al. Glutamate levels in cerebrospinal fluid in amyotrophiclateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci, 2002, 193: 73~78
40 Bendotti C, Tortarolo M, Suchak SK,et al. Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. J Neurochem, 2001, 79: 737~746
41 Howland DS, Liu J, She Y, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA, 2002, 99: 1604~1609
42 Siklos L, Engelhardt J, Harati Y, et al. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis, Ann Neurol, 1996, 39: 203~216
43 Siklos L, Engelhardt JI, Alexianu ME, et al. Intracellular calcium parallels motoneuron degeneration in SOD-1mutant mice. J Neuropathol Exp Neurol, 1998, 57: 571~587
44 Dykens JA. Isolated cerebral and cerebellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: implications for neurodegeneration. J Neurochem, 1994, 63: 584~591
45 Stout AK, Raphael HM, Kanterewicz BI, et al. Glutamate-induced neuron death requires mitochondrial calcium uptake. Nat Neurosci, 1998, 1: 366~373
46 Carriedo SG, Sensi SL, Yin HZ, et al. AMPA exposures induce mitochondrial Ca2+ overload and ROS generation inspinal motor neurons in vitro. J Neurosci, 2000, 20: 240~250
47 Trotti D, Rossi D, Gjesdal O, et al. Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem, 1996, 271: 5976~5979
48 Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidantvulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci, 1998, 19: 328~334
49 Trotti D, Rolfs A, Danbolt NC, et al. SOD1mutants linked to amyotrophic lateral sclerosis selectively inactivate a glial glutamate transporter. Nat Neurosci, 1999, 2: 427~433
50 Pedersen WA, Fu W, Keller JN, et al. Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients. Ann Neurol, 1998, 44: 819~824
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