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被称为多谷氨酰胺疾病的神经系统疾病群的分子基础。它们都是遗传性的，以神经系统进行性恶化为特征的成人发病疾病。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。这些疾病的基因突变导致产生一种含有异常长链氨基酸谷氨酰胺的蛋白质，这种蛋白质使突变蛋白具有对神经元有毒的功能。越来越多的证据表明，转录失调可能是多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展型聚谷氨酰胺的主要靶点。因此，我们假设聚谷氨酰胺诱导的神经变性是由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，转录的改变最终导致细胞死亡机制的不适当动员，从而导致神经变性。为了验证这些假设，以下具体目标将被解决：具体目标1)使用果蝇模型系统验证我们的工作假设，即扩展聚谷氨酰胺的毒性是组蛋白乙酰化缺陷的结果。特异性目的2)在果蝇多谷氨酰胺病模型中鉴定参与介导神经退行性变的基因骨干。特异性目的3)确定多谷氨酰胺诱导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.