Mechanism of SOD1-linked ALS studied in C elegans and mouse models

神经退行性变是一种知之甚少的生物学现象，也是一个日益严重的公共卫生挑战 for our ageing老化society社会.因果性遗传突变的发现加速了人们对基因突变的分子机制的理解。 这些疾病的机制。铜/锌超氧化物歧化酶（SODI）的突变与一种 肌萎缩侧索硬化症（ALS）的一个子集，一种破坏性的运动神经元退行性疾病，导致 进行性瘫痪了解大量的S 0 D1突变，大部分是单个氨基酸， 变化，导致特定的运动神经元变性可能提供重要的洞察力，更普遍的 散发性ALS。为此，我们已经开发了新的SODI转基因C。线虫和老鼠 神经元功能障碍和运动缺陷。蛋白质;错误折叠和聚集，一个越来越常见的 与主要的神经退行性疾病的关联，神经退行性疾病是无脊椎动物和 哺乳动物模型。模型的初步特征追踪了行为缺陷到突触 功能障碍在这里，我们建议联合收割机使用遗传上易处理的C。秀丽线虫和老鼠 模型来剖析疾病的机制，包括蛋白质聚集的作用。该说明可 有助于更好地了解ALS以及一般的神经退行性疾病。

Neurodegeneration is a poorly understood biological phenomenon and an increasing public health challenge for our aging society. Discoveries of causal genetic mLitations have accelerated understanding the molecular mechanisms of these diseases. Mutations in Cu/Zn superoxide dismutase (SODI) have been linked to a subset of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease that leads to progressive paralysis. Understanding how a large number of S0D1 mutations, mostly single amino acid changes, cause the specific motor neuron degeneration may provide important insight into more prevalent sporadic ALS. To this end, we have developed novel SODI transgenic C. elegans and mice that exhibit neuronal dysfunction and locomotor defects. Protein;misfolding and aggregation, an increasingly common association with major neurodegenerative diseases, lare a main feature of both the invertebrate and the mammalian animal models. Initial characterization ofthe models traced the behavioral defects to synaptic dysfunctions. Here we propose to combine the use of the genetically tractable C. elegans and the mouse models to dissect the disease mechanism, including the role of protein aggregation. The elucidation may contribute to a better understanding of ALS as well as neurodegenerative diseases in general.