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

项目总结 三核苷酸重复障碍是一类由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)，一种罕见的致命神经退行性疾病， 都是遗传的。HD是由亨廷顿(HTT)中CAG三核苷酸序列的扩展重复引起的 吉恩。超过36个CAG重复的扩增会导致致病转录本和蛋白质导致迟发 起病，但严重的晚期神经退行性变。整个CAG重复序列的长度 基因组是不稳定的，有很高的世代扩展潜力。虽然高清大部分是遗传的，但一小部分 病例的比例是由CAG重复序列的零星扩展引起的。约60%的方差在 HD症状的出现可归因于一个人携带的CAG重复次数；更多的CAG扩展 与较早发病有关。在出现症状的持续时间中，超过一半的剩余变异性 被归因于仍未被发现的环境因素。环境中的化学品暴露可能会导致- 归因于重复不稳定和随后的散发性形式的三核苷酸重复疾病，如HD。在- 确实，化学诱导的氧化应激会导致CAG重复扩增突变。我们之前演示过 线粒体抑制杀虫剂引起小鼠神经元氧化应激并诱导基因表达信号。 HD的性质。这一类杀虫剂中的一种，吡虫菊酯，在食物上的使用量非常高，以抑制 真菌病原体。预测的人类暴露水平表明，它们足以抑制人类有丝分裂素- 因此，DRIA可能会增加HD疾病的风险和严重性。我们的初步结果表明， 吡咯菌酯可导致培养细胞中CAG的重复扩增。我们将检验吡虫菊酯的假设 加速HD的进程，但也能够在非携带者中产生新的致病重复扩张 艾尔斯。我们将应用一套不同的分子、组织病理学和行为学工具来描述HD 在一个被广泛接受的HD小鼠模型中，在整个生命过程中暴露于吡菌酯的表型。我们的 研究结果将为为三叉神经症的家庭危险人群制定预防策略提供必要的基础。 核苷酸重复紊乱。此外，我们的工作重新定义了环境化学品作为诱变剂和 扩大了他们作为典型遗传病贡献者的角色。

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.