C. ELEGANS MODEL FOR POLYGLUTAMINE TOXICITY

描述（来自申请人的摘要）：八种神经退行性疾病 是由蛋白质中谷氨酰胺束的扩张引起的，包括脊髓 小脑共济失调、DRPLA、亨廷顿病和肯尼迪病。是 不清楚为什么扩展的多聚谷氨酰胺束是有毒的，并且没有治疗方法 对于这些疾病。我们开发了一个C。elegans过表达模型 表达亨廷顿蛋白片段的多聚谷氨酰胺神经毒性 我们将评估突变型共济失调蛋白-1和3的毒性活性 在同样的C。秀丽神经元。pqe-1特异性强突变 增强C.优雅我们将克隆并鉴定pqe-1。我们 将表征和克隆另外的增强子基因，并将鉴定， 表征和克隆抑制基因。相应的蛋白质是 在亨廷顿氏病和其他疾病中的聚谷氨酰胺毒性的候选调节剂 多谷氨酰胺病 我们将在C中产生突变。亨廷顿蛋白、共济失调蛋白-1和 共济失调蛋白-3，以解决其在神经系统和神经变性中的作用。 这些基因之间的关系，多聚谷氨酰胺毒性，凋亡 途径和其他候选基因将被评估。我们将识别人类 在我们的遗传筛选中鉴定的增强子和抑制子基因的同源物， 评估其在其他模式生物中多聚谷氨酰胺毒性中的作用， 这些候选基因与人类疾病的相关性。

DESCRIPTION (From the Applicant's Abstract): Eight neurodegenerative diseases are caused by expansion of glutamine tracts in proteins, including spinal cerebellar ataxias, DRPLA, Huntington's disease and Kennedy's disease. It is unclear why expanded polyglutamine tracts are toxic and there is no treatment for these diseases. We have developed a C. elegans overexpression model for polyglutamine neurotoxicity by expressing huntingtin protein fragments in neurons and we will assess the toxic activity of mutant ataxin-1 and ataxin-3 in these same C. elegans neurons. Mutation of pqe-1 specifically and strongly enhances polyQ toxicity in C. elegans. We will clone and characterize pqe-1. We will characterize and clone additional enhancer genes and will identify, characterize and clone suppressor genes. The corresponding proteins are candidate modifiers of polyglutamines toxicity in Huntington's and other polyglutamine diseases. We will generate mutations in C. elegans homologs of huntintin, ataxin-1 and ataxin-3 to address their role in the nervous system and in neurodegeneration. The relationship between these genes, polyglutamine toxicity, the apoptotic pathway and other candidate genes will be assessed. We will identify human homologs of enhancer and suppressor genes identified in our genetic screens and assess their role in polyglutamine toxicity in other model organisms to address the relevance of these candidate genes to human disease.