TRANSGENIC MODELS OF MOTOR NEURON DISEASE

肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是运动神经元病的经典类型 疾病（MND）。 与阿尔茨海默病（AD）一样，ALS是一种慢性疾病， 通常发生在晚年的进行性神经元紊乱。 研究 的ALS与AD相关有几个原因：ALS和AD的子集 家族性常染色体显性遗传病与错义 21号染色体上的基因突变;在这两种疾病中， 选择性地影响神经细胞群;选择性的机制 这些神经元组的脆弱性和功能障碍/死亡不是 然而，在这两种疾病中，我们都很清楚;在ALS和AD中，受影响的神经元 发展成细胞骨架病变并最终死亡;这些神经元 已经提出病理是由几种机制介导的， 包括兴奋性毒性、氧化损伤和钙内流; 除了几个例外，小动物模型尚不可用; 去神经支配有时发生在ALS受试者中，并且没有 有效治疗ALS或AD。 性格，动力， 细胞病理学的演变和细胞凋亡的机制 功能障碍/死亡难以在人类中研究。 因为 介入性生物方法在人类中是不可能的， 因为尸检分析通常限于严重的终末期疾病， 动物模型至关重要。 最近发现， Cu/Zn超氧化物歧化酶（SOD 1）基因与家族性ALS（FALS）相关 这表明，将SOD 1突变引入 小鼠可以产生一种FALS模型。 这些老鼠可以用来测试 这些突变在疾病中的作用，以建立特征和 与这些突变相关的病理演变，以澄清 运动神经元脆弱性和功能障碍的机制，并测试 新疗法 在本项目中，我们将分析 突变对体外系统中SOD 1活性和神经元的影响 SOD 1突变的转基因小鼠。 我们将使用的策略， 被证明是非常有价值的调查机制， 其他神经元疾病模型中的神经元功能障碍/死亡。 我们 我认为，本项目中概述的研究转基因的方法 与其他研究中描述的相似， 我们阿尔茨海默病研究中心的项目，将大大提高 我们对这种神经退行性疾病的了解， 在确定发病机制和提供模型进行测试方面的价值 治疗迟发性、年龄相关的神经系统遗传性疾病 系统

Amyotrophic lateral sclerosis (ALS) is the classical form of motor neuron disease (MND). Like Alzheimer's disease (AD), ALS is a chronic progressive neuronal disorder that usually occurs in late life. Studies of ALS are relevant to AD for several reasons: subsets of ALS and AD patients have familial autosomal dominant disease linked to missense mutations of genes on chromosome 21; in both disorders, disease processes selectively affect groups of nerve cells; the mechanisms of selective vulnerability and dysfunction/death of these groups of neurons are not yet well understood in either disease; in ALS and AD, affected neurons develop cytoskeletal pathology and eventually die; these neuronal pathologies have been suggested to be mediated by several mechanisms, including excitotoxicity, oxidative damage, and calcium influx; with several exceptions, small animal models are not yet available; denervation sometimes occurs in subjects with ALS, and there are no effective therapies for ALS or AD. The Character, dynamics, and evolution of the cellular pathology and the mechanisms of cell dysfunction/death are difficult to study in humans. Because interventional biological approaches are not possible in humans and because autopsy analyses are usually limited to severe end-stage disease, animal models are essential. The recent discovery that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are linked to familial ALS (FALS) suggest that transgenic strategies that introduce SOD1 mutations into mice can produce a model of FALS. These mice can be used to test the roles of these mutations in disease, to establish the characteristics and evolution of the pathology associated with these mutations, to clarify the mechanisms of motor neuron vulnerability and dysfunction, and to test novel therapies. In this Project, we will analyze the effect of the mutation on SOD1 activity in in vitro systems and on neurons in transgenic mice with SOD1 mutations. We will use strategies that have proven to be of great value in investigations of the mechanisms of dysfunction/death of neurons in other models of neuronal disease. We think that the approaches outlined in this Project to study transgenic mice with FALS mutations, which parallel those described in other projects of our Alzheimer's Disease Research Center, will greatly enhance our understanding of this neurodegenerative disease and will be of great value in identifying pathogenetic mechanisms and providing models to test therapies in late-onset, age-associated genetic diseases of the nervous system.