Project 3

项目总结（见说明）： SODI连锁ALS的转基因小鼠模型显示出许多相似的表型。首先，所有表达 高水平的突变蛋白[>内源性的3倍）发展为进行性麻痹性疾病。二是 在症状发作和人体终点之间的间隔，脊髓组织大量积聚， 不溶于洗涤剂的突变体SOD 1的聚集体。第三，在出现症状之前， 在脊髓中出现异常，包括肌肉神经支配的丧失、星形胶质细胞增生和 运动神经元形态学在前一个奖项期间，我们发现了内在能力之间的联系， 突变体SOD1形成大的、可沉积的聚集体的能力以及疾病在人类中进展的速率。为 例如，SOD1中的A4V突变与短期疾病相关，并且非常易于聚集。通过 相比之下，SOD1中的H46R突变与长持续时间（> 15年）的疾病相关，并且与高持续时间（> 15年）的疾病相关性要小得多。 易于形成聚集体。在本申请中，我们提出了4个目的，其将阐明突变体SOD1在细胞内的作用。 聚集和/或多聚化。目标1将直接跟进 第一个奖励期，以进一步研究突变体SOD1的聚集与疾病之间的关联 进展我们将确定SODl中的所有疾病相关突变是否引起蛋白质聚集， 使用多因素方法来确定聚集和疾病进展之间的关系。目的2 将通过改变突变蛋白质直接测试突变SOD1聚集在疾病进展中的作用 在转基因SOD1小鼠模型中的聚集。将使用多种方法来操纵 小鼠中的突变SOD1。目的3将确定定义突变体SOD1多聚化和突变体SOD2多聚化之间的关系。 疾病的演变。目的4将寻求确定共表达野生型p53的机制。 突变小鼠中的人SOD1加速疾病的发作。野生型SOD1的高水平表达增强了细胞的增殖。 加速疾病发作并可能影响疾病进展速度的毒性。结束时 通过这些研究，我们将阐明诱导早期疾病表型的SOD1蛋白的性质， 确定了突变体SOD1多聚化在疾病进展中的作用。

PROJECT SUMMARY (See instructions): Transgenic mouse models of SODI-linked ALS show a number of similar phenotypes. First, all mice that express the mutant protein at high levels [>3 fold over endogenous) develop a progressive paralytic disease. Second, in the interval between the onset of symptoms and human endpoint, spinal cord tissues accumulate large, detergent-insoluble, aggregates of mutant SODl. Third, prior to the onset of symptoms, a number of pathologic abnormalities appear in spinal cord, including loss of muscle innervation, astrogliosis, and pathologic changes in motor neuron morphology. In the prior award period, we uncovered a link between the inherent ability of mutant SODl to form large, sedimentable, aggregates and the rate at which disease progresses in humans. For example the A4V mutation in SODl is associated with short duration disease and is highly prone to aggregate. By contrast the H46R mutation in SODl is associated with disease of long duration (>15 years) and is much less prone to form aggregates. In the present application, we propose 4 Aims that will clarify the role of mutant SODl aggregation, and/or multimerization, in that pathogenesis of ALS. Aim 1 will directly follow up on studies of the first award period to further investigate the association between aggregation of mutant SODl and disease progression. We will determine whether all disease-associated mutations in SODl cause protein aggregation and use a multifactoral approach to determine the relationship between aggregation and disease progression. Aim 2 will directly test the role of mutant SODl aggregation in disease progression by altering mutant protein aggregation in transgenic SODl mouse models. Multiple approaches will be used to manipulate aggregation of mutant SODl in mice. Aim 3 will determine define the relationships between mutant SODl multimerization and the evolution of disease. Aim 4 will seek to determine the mechanism by which co-expression of wild-type human SODl in mutant mice hastens the onset of disease. High level expression of wild-type SODl augments a toxicity that hastens the onset of disease and may affect the rate of disease progression. At the conclusion of these studies, we will have clarified the nature of SODl proteins that induce early disease phenotypes and determined the role of mutant SODl multimerization in disease progression.