Neurodegeneration and Proteotoxicity Dissected in C. elegans and Mammals

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS）是一种以运动神经元变性为特征的进行性神经退行性疾病。在某些形式的ALS中，蛋白质错误折叠和特定蛋白质的聚集，包括Cu/Zn超氧化物歧化酶（SOD1），与运动神经元变性有关。通过涉及基因工程小鼠模型的研究，对包括ALS在内的神经退行性疾病的理解取得了相当大的进展。然而，分析小鼠年龄依赖性神经变性所需的复杂性、时间和资源限制了小鼠系统用于大规模遗传和化学筛选的有效性。为了克服这些限制，该实验室开发并验证了秀丽隐杆线虫（一种快速生长的透明线虫，适合分子遗传分析）中ALS的更简单的无脊椎动物模型。这个秀丽隐杆线虫模型概括了人类ALS的主要特征，包括明显的运动缺陷和神经元中的蛋白质聚集病理。该模型使用无偏和大规模的遗传筛选，以有效的方式解剖sod1诱导的神经变性的机制成为可能。这些研究已经鉴定出影响和调节ALS疾病模型中神经变性和蛋白质聚集的基因。该项目的目标是确定和阐明ALS发病机制受这些新型修饰剂影响的机制。具体目标是确定和表征影响和调节疾病的关键基因，描绘影响发病机制的途径，并将研究结果扩展到相关的哺乳动物系统。拟议的研究将哺乳动物系统与秀丽隐杆线虫的创新和有前途的方法结合起来，有望为神经退行性疾病的基本机制提供见解，从而可能导致治疗ALS和相关神经退行性疾病的新方法。

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. In some forms of ALS, protein misfolding and aggregation of specific proteins, including Cu/Zn superoxide dismutase (SOD1), have been implicated in motor neuron degeneration. Considerable advances in the understanding of neurodegenerative diseases, including ALS, have been made through studies involving genetically engineered mouse models. However, the complexity, time, and resources required for analyzing age-dependent neurodegeneration in mice limit the usefulness of mouse systems for large-scale genetic and chemical screens. To overcome these limitations, this laboratory has developed and validated a simpler invertebrate model of ALS in Caenorhabditis elegans, a fast- growing, transparent nematode that is amenable to molecular genetic analysis. This C. elegans model recapitulates the major features of human ALS, including a pronounced locomotor defect and the protein aggregation pathology in neurons. This model has made it possible to dissect the mechanism of SOD1-induced neurodegeneration in an efficient manner, using unbiased and large-scale genetic screens. These studies have led to the identification of genes that influence and modulate the neurodegeneration and protein aggregation in ALS disease models. The goal of the proposed project is to identify and elucidate the mechanisms through which ALS pathogenesis is influenced by these novel modifiers. The specific aims are to identify and characterize key genes that influence and modulate the disease, to delineate the pathways through which the pathogenesis is influenced, and to extend the findings to related mammalian systems. The proposed studies, which combine mammalian systems with innovative and promising approaches using C. elegans, are expected to provide insight into fundamental mechanisms of neurodegeneration that may lead to novel approaches for treating ALS and related neurodegenerative diseases.