Environmental drivers of trinucleotide repeat instability and Huntington's disease onset

项目摘要 三核苷酸重复序列障碍是一类由DNA重复变化定义的神经系统疾病。许多 三核苷酸重复疾病，包括亨廷顿病（HD），一种罕见和致命的神经变性疾病， 都是遗传的HD是由亨廷顿蛋白（HTT）中CAG三核苷酸序列的扩展重复引起的。 基因大于36个CAG重复序列的扩增导致致病性转录本和蛋白质引起迟发性 发病，但严重和终端形式的神经变性。整个CAG重复序列的长度 基因组是不稳定的，具有跨代扩展的高潜力。虽然HD主要是遗传的，但一小部分 一部分病例是通过CAG重复序列的零星扩增而出现的。大约60%的方差 HD症状的发作可归因于一个人携带的CAG重复的数量;更多的CAG扩展 与早期发病有关。在症状发作持续时间的剩余变异性中， 这些都是由环境因素造成的，至今尚未被发现。环境化学品暴露可能会导致- 由于重复不稳定性和随后的散发形式的三核苷酸重复疾病，如HD。在- 事实上，化学诱导的氧化应激导致CAG重复扩增突变。我们先前表明 线粒体抑制杀虫剂引起小鼠神经元的氧化应激，并引发基因表达， HD的性质该农药类别的一员吡唑醚菌酯在食品中的施用量非常高，以抑制 真菌病原体预测的人类暴露水平表明，它们足以抑制人类线粒体- 因此，可能会导致HD疾病的风险和严重程度。我们的初步结果表明， 吡唑醚菌酯引起培养细胞中CAG重复扩增。我们将检验吡唑醚菌酯 加速了HD的进程，但也能够在非携带者中产生新的致病性重复扩增， 呃。我们将应用一套不同的分子，组织病理学和行为学工具来表征HD 在广泛接受的HD小鼠模型中，吡唑醚菌酯在整个生命过程中暴露后，我们 结果将为那些有trinu家族风险的人建立预防策略提供必要的基础， 氯肽重复序列紊乱。此外，我们的工作重新定义了环境化学品作为诱变剂的作用， 扩大了他们作为典型遗传疾病的贡献者的作用。

PROJECT SUMMARY Trinucleotide repeat disorders is a class of neurological diseases defined by repetitive changes in DNA. Many trinucleotide repeat disorders including Huntington’s disease (HD), a rare and fatal neurodegenerative disease, are inherited. HD is caused by expanded repeats of the CAG trinucleotide sequence in the Huntingtin (HTT) gene. Expansions greater than 36 CAG repeats leads to a pathogenic transcript and proteins causing a late onset, but severe and terminal form of neurodegeneration. The length of the CAG repeat sequences throughout the genome is unstable with a high potential to expand across generations. While HD is mostly inherited, a small proportion of cases arise through sporadic expansion of CAG repeats. Approximately 60% of the variance in the onset in HD symptoms is attributable to the number of CAG repeats a person carries; more CAG expansions are associated with earlier onset. Over half of the remaining variability in the duration to symptom onset has been attributed to environmental factors that remain undiscovered. Environmental chemical exposure could con- tribute to repeat instability and subsequently, sporadic forms of trinucleotide repeat disorders such as HD. In- deed, chemical-induced oxidative stress causes CAG repeat expansion mutations. We previously demonstrated that mitochondria inhibiting pesticides cause oxidative stress in mouse neurons and elicit gene expression sig- natures of HD. One member of this pesticide class, pyraclostrobin, is applied at very high levels on food to inhibit fungal pathogens. Predicted human exposure levels suggest that they are sufficient to inhibit human mitochon- dria and therefore, could contribute to HD disease risk and severity. Our preliminary results demonstrate that pyraclostrobin causes CAG repeat expansion in cultured cells. We will test the hypothesis that pyraclostrobin accelerates the course of HD, but is also capable of producing new pathogenic repeat expansions in non-carri- ers. We will apply a diverse set of molecular, histopathological, and behavioral tools to characterize the HD phenotypes in a widely accepted mouse model of HD upon pyraclostrobin exposure across the life course. Our results will provide the foundation necessary to establish prevention strategies for those at familial risk for trinu- cleotide repeat disorders. Moreover, our work re-defines the role of environmental chemicals as mutagens and expands their role as contributors to canonical genetic diseases.