人体生物化学及疾病

,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,2,大学教育的意义,关于学习：,使青年们主动学习，通过发现问题并解决问题，养成独立思考能力和判断能力。抛弃“听话”，追求“创造”,关于成长：,使青年们在独立生活中，学习维护自己的利益，同时维护他人利益，求得共赢。由此爱己亦爱人，做一个有良知、有良好文明素质的人。,关于未来（事业，生计）：,使青年们在历史与现实的比对中，探寻内心，确定人生方向，并为之努力（选择：,1,，最喜欢的, 2,，最擅长的, 3,，社会最需要的, 4,，最有条件的为方向）。,3,commander,4,神经系统,是由神经组织相互联系构筑的一个错综复杂的电及化学信号网络,借此协调控制人的运动、感觉、语言、记忆、思维和情绪。,第一节 概述,以人的大脑为例：,神经元总数,1000,亿；神经胶质细胞,50X,（,1000,亿）；,mRNA,表达量比其他器官高,3,5,倍（结构复杂，功能活跃）,任何时间空间点，大脑结构或功能的的紊乱都可能引发神经系统疾病或精神疾病。,5,神经系统,中枢神经系统,脑,脊髓,周围神经系统,颅神经,(12,对,),脊神经,(31,对,),内脏神经,（宏观）,6,神经组织,（微观）,神经元（神经细胞）,神经胶质细胞及间质,小胶质细胞,星形胶质细胞,少突胶质细胞,7,神经元的结构,8,维持神经系统正常功能所需条件：,神经组织的正常生长,能量,营养及神经生长,(,营养,),因子,神经细胞的外在环境,（脑脊液）,神经细胞间的信号传递,（神经递质及其受体）,9,一、脑脊液与血脑屏障,1,、形成：,主要由侧脑室脉络丛生成。,（一）脑脊液的形成与功能,经室间孔流至第三脑室，与第三脑室脉络丛产生的脑脊液一道，经中脑水管流入第四脑室，再汇合该室脉络丛产生的脑脊液经第四脑室正中孔和外侧孔流入蛛网膜下隙，再流向大脑背面，经蛛网膜颗粒渗透到硬脑膜窦内，回流入血液中,脑脊液的循环,10,11,(cerebrospinal fluid),12,2,、脑脊液的主要功能：,运送营养物质，带走代谢产物,保护作用，避免震荡冲击,脑内接触脑脊液神经元感受内环境变化的窗口及其分泌激素的运输通道,调整颅内压,脑脊液的成分特点：,微量的蛋白质,较少的葡萄糖,较多的电解质,13,14,血-脑之间选择性阻止各种物质由血入脑的“屏障”，使脑组织处于相对稳定的内环境。,2,、血脑屏障,毛细血管内皮细胞,基膜,星形胶质突起形成的血管鞘,（1）结构,15,（2）血脑屏障的选择通透性,1）通过血脑屏障的方式,扩散,水、气体和高脂溶性物质,载体转运,葡萄糖、氨基酸和各种离子成分,2,）蛋白质不易通过,16,二、神经组织的生物化学特点,（一）糖代谢,正常条件下，神经组织最重要和唯一有效的能量来源。,糖原含量少。,糖代谢方式：,主要是有氧氧化，其次是糖酵解。,17,（二）脂类代谢,除脂肪组织外，神经系统是含脂质最多的组织。,脑组织以类脂为主，包括甘油磷脂、鞘脂、胆固醇等。,饥饿时酮体可部分代替葡萄糖供能。,18,（三）蛋白质代谢,神经组织蛋白质含量丰富,包括清蛋白、球蛋白、核蛋白和神经角蛋白等。,氨基酸,脑,(g/ml),血浆,(g/ml),谷氨酸,10.6,0.05,谷氨酰胺,4.3,0.7,-,氨基丁酸,2.3,-,色氨酸,0.05,0.05,氨基酸代谢,19,（四）核酸代谢,脑中,RNA,含量特别高。,（五）水和电解质代谢,脑和脊髓含水量丰富。,神经元含多种离子通道，功能活跃。,20,（六）能量代谢,脑耗氧量明显高于其他组织的耗氧量，主要由葡萄糖有氧氧化提供。（对缺氧和缺糖极敏感）,脑内,ATP,处于高水平，迅速生成和利用。,21,三、神经递质的生物化学,神经递质（,neurotransmitter）：,神经元间或神经元与靶细胞（肌肉、腺细胞）间起作用的化学物质。,分类,主要神经递质,胆碱类,乙酰胆碱,单胺类,儿茶酚胺、肾上腺素、去甲肾上腺素、多巴胺,吲哚胺,5-,羟色胺,氨基酸类,兴奋性氨基酸：谷氨酸、门冬氨酸,抑制性氨基酸：,-,氨基丁酸、甘氨酸,神经肽类,下丘脑释放激素、神经垂体激素、阿片肽、,垂体肽、脑肠肽等,气体类,一氧化碳、一氧化氮,22,23,几种重要的神经递质：,乙酰胆碱,甘氨酸,谷氨酸,多巴胺,去甲肾上腺素,肾上腺素,5-,羟色胺,组胺,-,氨基丁酸,24,四、神经生长因子、营养因子、抑制因子,生长因子,是一类影响神经元生存和发育、诱导神经元分化的生物活性物质（多肽），对神经元在发育时的生长、分化，以及成年神经元的维持具有重要作用。,营养因子,是一组能促进神经细胞生长、增殖、延长其生存时间并调节神经细胞分化和形态重塑的特异性内源性信号蛋白,。,抑制因子,神经纤维的生长受其环境中起营养作用的信号因子和抑制性信号因子的共同调控。,名称,靶细胞,生理作用,神经生长因子,神经元,调节神经元前体细胞增殖和分化,脑源性神经营养因子,神经元,维持和促进多种神经元的发育分化和生长再生、挽救损伤的脊髓运动神经元和感觉神经元,神经营养因子,-3,少突胶质细胞、神经元,对三叉神经节部分神经原和交感神经节有生物学效应,神经营养因子,-4/5,少突胶质细胞、神经元,促进神经元的生长、分化,胶质细胞系源性神经营养因子,星形细胞、施万细胞,保护和修复各种原因造成损伤的神经细胞、促进正常神经元发育,睫状神经营养因子,神经元,支持多种类型神经元存活,胰岛素样生长因子,少突胶质细胞、神经元,参与调节中枢神经系统和周围神经系统神经元的生长和发育,成纤维细胞生长因子,星状细胞神经元、少突神经胶质细胞,促进损伤神经元的修复与再生,血小板源性生长因子,星形细胞、少突神经胶质细胞,与神经系统的发育及成熟有关,转化生长因子,神经元,对多种原因引起的神经损害有保护作用,Collapsin-1,神经元,引起背根神经节（,DRG,）的生长冠萎缩,Neuropilin,神经元,具有轴突定向和控制神经元在中枢神经系统迁移的作用,25,26,第二节 神经、精神疾病的生物化学,神经系统疾病,：,是指脑、脊髓及周围神经由于感染、血管病变、外伤、肿瘤、中毒、免疫障碍、变性、遗传、营养缺陷和代谢障碍等因素所致的疾病。,基本病理改变,神经元变性,27,精神疾病,：,是以,精神活动,失调或紊乱为主要表现的一类疾病。,28,神经变性的生物化学基础,神经变性病：,以神经元变性为主要病理改变。,特点：,中枢神经系统中某个或某些特定的部位的神经元进行性变性以至坏死，伴有胞质内结构紊乱，或出现包涵体等，但无炎症或异常物质的累积。,29,（一）基因突变,30,（二）能量代谢缺陷,线粒体,DNA,缺陷,线粒体功能障碍,16569bp,31,32,在人体各个细胞都存有线粒体,单个细胞包含,200 2000,个线粒体,但是不同组织的细胞内线粒体的数量是不同的,而在相同组织的细胞内线粒体数量是接近的,缺少组蛋白的保护与有效的校读系统, mtDNA,极易受到氧化磷酸化过程中产生的活性氧簇,( reactive oxygen species, ROS),的损害而突变,其突变率较核,DNA,高,10 100,倍,线粒体,DNA,的修复机制不完善,效率低下,线粒体,DNA,的突变可导致线粒体功能缺陷,线粒体,DNA,只有过度复制产生数量惊人的拷贝才能补偿此缺陷,2004,年发现,mtDNA,也能发生重组。,线粒体基因的特点,33,（三）自由基分子代谢,自由基增多：,线粒体损伤,神经细胞,DNA,损伤,可促进兴奋性氨基酸释放,自由基（,free radical）,指在原子核外层轨道上带有不配对的电子。,SOD,等,清除,superoxide dismutase,34,（四）兴奋性氨基酸释放过度,作用于相应的受体,诱使离子通道开放,通过离子触发一系列对细胞造成损害的反应，产生毒性效应。,谷氨酸、天冬氨酸、红藻氨酸等,35,（五）异常钙离子通道开放与,Ca,2+,效应,（六）异常蛋白磷酸化和蛋白糖基化作用,（七）神经营养因子缺乏,（,八）神经细胞凋亡（,apoptosis）,36,第三节 神经和精神疾病生物化学诊断,主要检测对象：,脑脊液 （,CSF,，,cerebrospinal fluid,）,一般性检查,神经递质的测定,脑脊液蛋白质的测定,酶的测定,37,（一）一般性检查,38,Ach,、,DA,及,HVA,、,5-HT,及,5-HTAA,、,GABA,、谷氨酸、神经肽等。,神经递质对中枢神经系统功能和精神活动起重要作用，某些神经系统的疾病及精神病可表现相应递质的变化。,（二）神经递质的测定,脑脊液中常用神经递质的检测及临床意义,递质名称,常用方法,参考值,临床意义,5-HT,(,5-,羟色胺,),高效液相色谱法、酶学分析法、荧光法等,20ng/ml,增高：颅脑外伤与脑血管疾病,降低：精神发育迟滞、,PD,患,者及抑郁型精神病等,5-HIAA,(,羟吲哚乙酸,),17.16.5ng/ml,谷氨酸,高效液相色谱法、荧光分光光度法、高压电泳法等,0.41,22.75,mol/dl,增高：精神分裂症等,降低：,PA,患者,GABA,(,-,氨基丁酸,),0,0.1,mol/dl,降低：癫痫病,P,物质,放射免疫法,增高：精神抑郁性患者,降低：帕金森病患者，但病,情严重时升高,-,内啡肽,增高：躁狂症、精神分裂症,降低：,AD,患者,脑啡肽,增高：癫痫患者,CCK,（,胆囊收缩素）,降低：精神分裂症,生长抑素,降低：,Alzheimer,型老年痴呆患者,39,40,总蛋白质,CSF,中蛋白质一部分是血浆中小分子量蛋白质经血脑屏障的毛细血管内皮细胞孔隙进入，以清蛋白为主，另部分为中枢神经系统本身合成，含量甚微。,一般成人超过450,mg/L,为病理性升高。,CSF,免疫电泳可提示血脑屏障渗透性改变的严重程度。,（三）脑脊液蛋白质的测定,脑脊液蛋白质定量,:,正常不同部位脑脊液蛋白质总量为：脑室液,50,150mg/L,；,脑池液,150,250mg/L,；腰池液,150,450mg/L,。,蛋白质电泳,:,蛋白组分,脑脊液,血清,临床意义,前白蛋白,2%,6%,0,增高：脑积水、脑外伤、脑萎缩及中枢神经系统退行性变,降低：脑内炎性疾病,白蛋白,44%,62%,56%,增高：椎管阻塞、脑血管疾病及脑肿瘤,降低：脑外伤,1,球蛋白,4%,8%,4.5%,增加：中枢神经系统感染,2,球蛋白,5%,11%,9.5%,球蛋白,13%,26%,12%,增加：肌萎缩及退行性病变,球蛋白,6%,13%,18 %,增高：脱髓鞘疾病及感染,41,蛋白质指数,蛋白质指数,白蛋白指数,=,CSF,白蛋白,mg/L,血清白蛋白,g/dL,IgG,和白蛋白比率,=,免疫球蛋白指数,=,CSFIgG mg/dL,血清白蛋白,g/dL,CSF,中白蛋白,mg/dL,血清,IgG g/dL,CSF,中,IgGmg/dL,CSF,中白蛋白,mg/dL,反映血脑屏障功能,诊断脱髓鞘疾病,反映鞘内,IgG,合成,42,43,特异性蛋白质,淀粉样蛋白,淀粉样蛋白前体,C,反应蛋白,微球蛋白,免疫球蛋白,神经组织特异蛋白,脑脊液中其他蛋白质的测定,髓鞘碱性蛋白：,含量增高是急性脑实质损伤和脱髓鞘改变的特异性生化指标。脑白质损害，尤其是多发性硬化病人增高。,胶质纤维酸性蛋白：,含量升高可见于脑星形细胞病、,Alzheimer,型痴呆、神经胶质瘤及海绵状脑病等。,S100,蛋白：,脑出血、脊髓压迫症、,Alzheimer,s,疾病、缺血性脑血管病、经肿瘤、病毒性脑炎及多发性硬化病人该蛋白增高。,寡克隆区带：,是检测中枢神经系统亚急性、慢性炎性病变鞘内免疫球蛋白合成的最可靠指标。,-,淀粉样蛋白：,升高对,Alzheimer,病诊断有重要价值，颅脑外伤亦可升高。,44,45,（四）酶活力测定,LDH,及其同工酶、,AST,、,CPK,、酸性磷酸酶、核糖核酸梅、多巴胺羟化酶、蛋白酶和鸟嘌呤酶、乙酰胆碱酯酶、葡萄糖苷酶等,CSF,中酶浓度一般不受中枢神经系统以外疾病的影响，活力测定可反映中枢神经系统病变。,脑脊液中酶的测定,神经元特异性烯醇化酶（,NSE,）,脑脊液中,NSE,含量的改变是神经元损伤的特异性生化标志。在脑梗死、癫痫、颅内高压、脑外伤、脑肿瘤等各种原因导致的中枢神经损害时，,NSE,含量均增加。,脑型肌酸激酶（,CKMB,）,CKMB,主要分布在脑内神经元，是神经损伤的特异性生化标志。在脑肿瘤、假肥大型肌营养不良症、癫痫、脑膜炎、脑损伤及脑血管性疾病时可增高。,其它酶类,46,分子生物检查方法,PCR,RFLP,分子杂交,目前，采用基因诊断的神经性疾病有苯丙酮尿症、,Alzheimer,病、亨迋顿病、线粒体肌病和脑肌病、神经肌肉病、遗传性共济失调、癫痫、神经纤维瘤病、,X,连锁智力低下及肝豆状核变性等。,（五）分子生物学诊断,47,48,PCR,（,Polymerase Chain Reaction,）,49,RFLP,（,restriction fragment length polymorphism,）,50,分子杂交（,molecular hybridization,）,51,帕金森病（,PD: Parkinsons disease）,亨廷顿病（,HD: Huntingtons disease,）阿尔茨海默病（,AD: Alzheimers disease,）,精神分裂症（,schizophrenia,）,肌萎缩性脊髓侧索硬化症（,ALS:,Amyotrophic lateral sclerosis,）,第四节 常见神经系统疾病,52,Parkinsons disease,53,诊断和试验,：,家族史,临床表现,病理检查,基因检测,10%,静息震颤肌强直随意运动减慢姿势不稳,54,黑质残存神经元胞质内出现嗜酸性包涵体，即路易小体,病理检查,端脑,中脑,脑干,55,无帕金森者,DNA,和氨基酸序列,帕金森患者,DNA,和氨基酸序列,基因检测,56,PARK1(SNCA),基因编码,-synuclein,蛋白,PARK2,基因编码,Parkin,蛋白,致病机制,家族性帕金森,1,型,遗传性帕金型青年帕金森病,56,57,中脑黑质多巴胺能神经元变性死亡,纹状体,DA,含量显著性减少,58,PD,病因及发病机制尚未明确，可能与社会因素、药物因素、患者因素等有关。,PD,病理改变为：中脑黑质致密部、蓝斑神经元色素脱失，黑质色素变淡及出现路易小体。,PD,神经生化改变为：中脑黑质致密部、蓝斑神经元脱失致上述部位及其神经末梢处多巴胺（,DA,）减少，（,DA,减少,70%,时产生,PD,临床表现），而黑质纹状体系统中与,DA,功能拮抗的乙酰胆碱（,ACH,）作用相对亢进，,DA,与,ACH,平衡失调。,59,Huntingtons Disease,一种常染色体显性遗传病，其发病率为,1/10000,。,60,临床表现,：,进行性舞蹈样徐动症强直，痴呆通常伴有癫痫,61,诊断和试验,：,阳性家族史,特征性临床表现,HD,基因的检测,62,分子遗传病理,异常基因产物为：,HD,基因中的,CAG,被转译为一段聚谷氨酸，该段在聚谷氨酸重复扩展时可致蛋白质的结构和生物化学特性改变。可能具有细胞毒性作用，致使神经元损伤。,62,63,Alzheimer disease,是一种进行性发展的致死性神经退行性疾病。,History of Alzheimers Disease,In November 1906, at a German psychiatrists meeting,Alois Alzheimer,presented the pathological findings on a brain of a 56 y.o. woman who died after a progressive dementia,64,The Case,Auguste Deter,This 51 y.o. woman was admitted to Frankfort hospital in 1901 for progressive dementia.,She was under the care of Dr. Alzheimer until her death in 1906. He did an autopsy, examined her brain & described the typical abnormalities of what would be called later Alzheimers Disease.,65,回间沟,脑回,脑室,66,68,诊断和试验,：,临床表现,神经影像,神经病理,基因检测,认知和记忆功能不断恶化,日常生活能力进行性减退,伴有各种神经精神症状和行为障碍。,69,基因检测,70,71,72,Pathophysiology from Tau,Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. A protein called,tau,stabilizes the microtubules when phosphorylated,In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating,neurofibrillary tangles,and disintegrating the neurons transport system.,73,Changes in Tau protein lead to microtubule desintegration,74,Genetics,The majority of Alzheimers Disease cases are sporadic,1/1000 cases are hereditary (autosomal dominant) and have usually an early onset,These are related to 3 genes:,Amyloid Precusor Protein (APP) and Preseniline 1 & 2 genes,Role of,Apolipoprotein E 4,allel?,75,76,Diagnosis of Alzheimers Disease The Future,Blood Tests,CSF,Imaging:,Volumetric MRI,Functionnal imaging: PET scan,Improving Diagnosis of AD by Blood & CSF Study,A complex comparative measurement of, 20 proteins,in the serum was shown to have high specificity & sensitivity for AD diagnosis,Measurement of,amyloid beta,and,tau,proteins levels in CSF can improve considerably the diagnosis of AD (sensitivity 94%-100%).,78,Molecular & Functional PET in AD,PET with,amyloid ligand,: The patient with AD has increased tracer binding in the frontal, parietal and temporal cortices.,Fluorodeoxyglucose PET,in the same subjects. The patient with AD demonstrates prominent hypometabolism, particularly in parietal cortex (arrows).,80,(PET: p,ositron emission tomography,正电子发射计算机断层扫描,),Increasing aged population,Projected increase in the number of cases of dementia, the elderly population, and the total population in,less developed countries,in the period 19902030,Henderson & Jorm 2000,Dementia,Elderly,Total,2020,2030,1990,2000,2010,Year,50,0,100,150,200,250,300,Increase over 1990 (%),81,82,精神分裂症（,schizophrenia）,以精神活动互不协调，脱离现实环境为特征，最常见的精神病。,Schizophrenia is a serious mental illness. People who suffer from it are unable to relate their thoughts and feelings to what is happening around them and often withdraw from society,83,临床表现,：,阳性行为,幻觉、错觉和怪异行为,阴性行为,社交回避和情绪迟钝等,84,84,85,86,发病机制,：,多巴胺功能亢进,遗传因素,87,2014,年,8,月开始的冰桶挑战赛,全称为“,ALS,冰桶挑战赛”（,ALS Ice Bucket Challenge,），要求参与者在网络上发布自己被冰水浇遍全身的视频内容，然后该参与者便可以要求其他人来参与这一活动。活动规定，被邀请者要么在,24,小时内接受挑战，要么就选择为对抗“肌肉萎缩性侧索硬化症”捐出,100,美元。该活动旨在是让更多人知道被称为渐冻人的罕见疾病，同时也达到募款帮助治疗的目的。 “,ALS,冰桶挑战赛”最先在全美科技界大佬、职业运动员中风靡，随后扩散至中国，科技界大佬纷纷响应，并流传至其他行业。,Amyotrophic lateral sclerosis,What is amyotrophic lateral sclerosis?,Descriptions of the disease date back to 1824 by Charles Bell,1869, Jean-Martin Charcot (the founder of modern neurology) linked it to the underlying neural problem.,It is a progressive neurological disease that affects the control of muscle movement due to its damaging affects on motor neurons in the spinal cord and the brain,Picture from the Memory & Aging Center,Significance of the Name of this Disease,A-myo-trophic comes from Greek,“A” = no/negative,“myo” = muscle,“trophic” = nourishment,“No Muscle Nourishment”,Lateral = defines location of the nerve cells that signal and control the muscles,Sclerosis = scarring and hardening in the degenerating region,Other common names for this disease:,Motor neuron disease,Charcots disease,Lou Gehrigs disease,Picture from the Neuromuscular website,Who was Lou Gehrig?,Lou Gehrig was a baseball player for the New York Yankees in the late 1920s and 1930s,What genes are related to ALS?,Copper/zinc Superoxide dismutase 1 (SOD1),Heavy neurofilament subunit (NEFH),Peripherin (PRPH),Dynactin (DCTN1),This disease affects SOD1 gene on chromosome 21,Mutations occurs at the SOD1 located on the long arm of Chromosome 21,Cu/Zn Superoxide dismutase 1 gene,Codes for the protein Cu/Zn Superoxide dismutase 1,Contains 5 exons and 4 introns,mRNA is 981 base pairs long,Structure of SOD1 Protein,SOD1 protein,Removes dangerous superoxide radicals by converting them to non-harmful substances,O,2, + O,2, + 2H,+, O,2,+ H,2,O,2,Protein contains 154 amino acids,Has one domain, SOD_Cu,Mutations in SOD1 protein,Several different mutations in this enzyme may all result in ALS, making the exact molecular cause of the disease difficult to ascertain,Mutations in SOD1 protein continued . . .,Some mutations in SOD1 associated with ALS:,R4V,G93A,G37R,G16S,Picture from The ALS Society of Canada,Nature and Characteristics of ALS,Forms:,Two types of ALS:,Sporadic no family history,Familial family history/background,90% of the known cases are sporadic,ALS continued . . .,Types of Familial,Autosomal dominant,Autosomal recessive,X-linked dominant,Sporadic,Who Gets ALS?,“According to the ALS CARE Database, 60% of the people with ALS in the database are men and 93% of patients in the database are caucasian.”,Normally occurs in people between 40 to 70 years of age,Also can occur in people in their 20s and 30s,From The ALS Association,Cause of ALS,Due to a mutation in SOD1, the superoxide radicals are not neutralized,The radicals attack the motor neurons and degrade them,Muscles are not able to be stimulated,Symptoms of ALS,First signs and symptoms (frequently overlooked),Twitching and cramping of muscles (especially in hands and feet),Stiffness,Weakness (especially in hands, arms and legs),Slurred speech,Picture taken from the National Institute of Aging,Symptoms continued . . .,Later signs and symptoms:,Difficulty chewing and swallowing,Shortness of breath,Muscle weakness due to wasting away of muscles,Causes muscles to become smaller,Respiratory failure,Paralysis,Picture from the ALS Association,This picture from the Neuromuscular website shows the wasting away of a persons hands and arms,Symptoms, or patterns of symptoms, are not the same for each ALS individual,However, progressive muscle weakness and paralysis are universally experienced,Since ALS attacks only motor neurons, the sense of sight, touch, hearing, taste, and smell are not affected,Patients usually only live 3 to 5 years after they are diagnosed,There are some cases; however, where individuals have lived 10 or more years,Diagnosing ALS,5,600 people in the US are diagnosed with ALS each year,ALS is a very difficult disease to diagnose,Blood tests, Urine tests, Spinal taps, x-rays, muscle or nerve biopsies, or a neurological examinations are administered,Medication for ALS,Rilutek (brand name) / riluzole (generic) slows progression of ALS,It is the only prescription drug for ALS,Approved in December 1995,From the MDA Publications,Hypothesis,The mechanisms that cause mutations in SOD1 that lead to ALS are unknown,Hypothesis #1,An increase or a decrease in the activity of SOD1 may cause ALS,We theorized that a decrease, rather than an increase, may be the cause of ALS.,Theory: decrease = produces more harmful free radicals,We searched NCBI in support for both an increase and a decrease in SOD1 activity,Support from NCBI,One study conducted by Rosen found that increased levels of expression of SOD1 in mice would produce excessive levels of hydrogen peroxide,From OMIM,Picture from The ALS Society of Canada,Support continued . . .,According to Kunst over-expression of normal SOD1 accelerates disease onset and progression,However, a decrease or increase in SOD1 activity is not sufficient to cause ALS in mice,From PubMed,Hypothesis #2,SOD1 may lose its ability to bind zinc (Zn), Copper (Cu), or both,This may cause SOD1 to lose its ability to process free radicals,From MDA Publications,Support from NCBI,Zinc and Copper = normal,Zinc removed = toxic,Zinc and Copper removed = non-toxic,Copper removed = not studied yet,Zinc that is bound to SOD1 may stabilize the protein,From PubMed,Support continued . . .,Zinc-deficient SOD1 produces more free radicals than it destroys,SOD1 mutant can not bind zinc as strongly as normal SOD1,谢谢观赏,