Comparative Modeling of Neurodegenerative Diseases

描述(申请人提供)：多种与年龄相关的神经退行性疾病[例如阿尔茨海默病(AD)、帕金森病(PD)、肌萎缩侧索硬化症(ALS)、亨廷顿病(HD)等]。与疾病特异性蛋白的聚集有关。编码这些蛋白的基因在这些疾病的某些家族形式中发生突变，这一发现有力地证明了这些聚集蛋白导致了这些疾病。然而，对于所有这些疾病，蛋白质聚集和细胞病理之间的关系还没有明确的建立。蛋白质聚集与这些疾病的共同联系是否反映了共同的潜在毒性机制，或者是细胞病理学的共同下游结果，也是未知的。我们将试图通过在转基因秀丽线虫模型系统中单独表达三种不同的疾病相关蛋白来确定这些蛋白聚集的分子后果。这些分子后果将通过基于DNA微阵列的基因表达研究和免疫共沉淀分析来确定。对不同疾病相关蛋白表达的分子反应的比较将有助于识别共同反应和疾病特异性反应。然后，我们将使用线虫可用的分子遗传工具来操纵这些分子反应，以确定它们在疾病蛋白毒性中的作用。这些研究将直接测试这些神经退行性疾病是否存在共同的潜在毒性机制。

DESCRIPTION (provided by applicant): Numerous age-associated neurodegenerative diseases [e.g., Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington's disease (HD), etc.] are associated with aggregation of disease-specific proteins. The finding that the genes encoding these proteins are mutated in some familial forms of these diseases strongly argues that these aggregating proteins cause these diseases. However, for all these diseases the relationship between protein aggregation and cellular pathology has not been clearly established. It is also unknown if the common association of protein aggregation with these diseases reflects a common underlying toxic mechanism, or, alternatively, a common downstream result of cell pathology. We will seek to identify the molecular consequences resulting from the aggregation of three different disease-associated proteins by individually expressing these proteins in a transgenic Caenorhabditis elegans model system. These molecular consequences will be determined by DNA microarray-based gene expression studies and co-immunoprecipitation analyses. Comparison of the molecular responses to expression of different disease-associated proteins will allow identification of common and disease-specific responses. We will then use the molecular genetic tools available in C. elegans to manipulate these molecular responses to determine their role in disease protein toxicity. These studies will directly test whether there is a common underlying toxic mechanism for these neurodegenerative diseases.