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

神经退行性变是一种鲜为人知的生物现象，也是一个日益严重的公共卫生挑战 为我们老龄化的社会服务。因果遗传突变的发现加速了对分子的理解 这些疾病的机制。铜/锌超氧化物歧化酶(SODI)的突变与 肌萎缩侧索硬化症(ALS)的亚型，这是一种毁灭性的运动神经元退行性疾病，导致 进行性瘫痪。了解大量S0D1突变，主要是单一氨基酸 改变，引起特定运动神经元变性可能提供重要的洞察更普遍 散发性肌萎缩侧索硬化症。为此，我们开发了新型SODI转基因线虫和小鼠，展示了 神经元功能障碍和运动缺陷。蛋白质；错误折叠和聚集，一种越来越常见的 与主要的神经退行性疾病有关，这是无脊椎动物和 哺乳动物动物模型。将行为缺陷追溯到突触的模型的初步表征 功能障碍。在这里，我们建议结合使用遗传上易驯化的线虫和老鼠 剖析疾病机制的模型，包括蛋白质聚集的作用。澄清可以 有助于更好地了解肌萎缩侧索硬化症以及神经退行性疾病。

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.