Molecular pathogenesis of polyglutamine disease

描述（由申请人提供）：本文所述研究的长期目标是确定称为多聚谷氨酰胺疾病的一组神经系统疾病的分子基础。它们都是遗传性的，成年后发病的疾病，其特征是神经系统的进行性恶化。这些疾病在分子水平上具有共同的遗传基础、共同的病理特征和共同的机制。这些疾病中的基因突变导致产生具有异常长的氨基酸谷氨酰胺的蛋白质，其赋予突变蛋白质对神经元有毒的功能获得。越来越多的证据表明，转录失调可能是多聚谷氨酰胺病的主要致病过程。我们自己的初步研究表明，组蛋白乙酰转移酶机制的组成部分可能是扩大聚谷氨酰胺的主要目标。因此，我们假设聚谷氨酰胺诱导的神经退行性变是由于组蛋白乙酰化缺陷导致的转录改变的结果。我们进一步假设，改变转录最终导致不适当的动员细胞死亡机制，有助于神经变性。具体目的1）使用果蝇模型系统来检验我们的工作假设，即扩增的聚谷氨酰胺的毒性是组蛋白乙酰化缺陷的结果。具体目的2）鉴定在多聚谷氨酰胺病的果蝇模型中参与介导神经变性的基因骨干。3）鉴定介导多聚谷氨酰胺诱导的神经元细胞凋亡的生化途径。

DESCRIPTION (provided by applicant): The long-term objective of the research described herein is to determine the molecular basis of a cluster of neurological disorders known as the polyglutamine diseases. They are all hereditary, adult-onset conditions characterized by progressive deterioration the nervous system. These diseases share a common genetic basis, common pathological features, and common mechanisms at the molecular level. The genetic mutation in these diseases leads to the production of a protein with an abnormally long tract of the amino acid glutamine that endows the mutant proteins with a gain-of-function that is toxic to neurons. A growing body of evidence suggests that transcriptional dysregulation may be a primary pathogenic process in polyglutamine disease. Our own preliminary studies suggest that components of the histone acetyltransferase machinery may be primary targets for expanded polyglutamine. Thus, we hypothesize that polyglutamine-induced neurodegeneration is a consequence of altered transcription resulting from defective histone acetylation. We hypothesize further that altered transcription ultimately leads to inappropriate mobilization of cell death machinery that contributes to neurodegeneration. To test these hypotheses, the following, specific aims will be addressed: Specific Aim 1) To test our working hypothesis that the toxicity of expanded polyglutamine is a consequence of defective histone acetylation using a Drosophila model system. Specific Aim 2) To identify the cadre of genes involved in mediating neurodegeneration in a Drosophila model of polyglutamine disease. Specific Aim 3) To identify the biochemical pathways that mediate polyglutamine-induced apoptosis in neuronal cell culture.