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

三核苷酸重复不稳定和亨廷顿病发病的环境驱动因素

基本信息

批准号：
10193294
负责人：
Brandon L Pearson
金额：
$ 24.3万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-21 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10193294
关键词：
Adenine Affect Alleles Antioxidants Ataxia Attention Behavioral Brain Cell Nucleus Cells Chemicals Chronic Consumption Counseling Cultured Cells Cytosine DNA DNA Sequence Data Disease Disease Progression Dose Environmental Exposure Environmental Risk Factor Expanded DNA Repeat Exposure to Food Foundations Fragile X Syndrome Gene Expression Profile Generations Genes Genetic Counseling Genetic Diseases Genome Goals Gonadal structure Guanine Human Human Cell Line Huntington Disease Huntington gene Impairment Incidence Individual Inherited Intervention Knock-in Lead Length Life Life Cycle Stages Mediating Mitochondria Mitotic Molecular Mosaicism Motor Mus Mutagens Mutation Myotonic Dystrophy Nerve Degeneration Neurocognitive Neurodegenerative Disorders Neurologic Neurons Onset of illness Oxidative Stress Pathogenicity Persons Pesticides Phenotype Prevalence Prevention approach Prevention strategy Primary Prevention Process Proteins Publishing Reporting Research Risk Role Secondary Prevention Severities Severity of illness Symptoms Testing Tissues Transcript Trinucleotide Repeat Expansion Trinucleotide Repeats Triplet Multiple Birth Variant Work advanced disease brain cell cell type dietary control disease phenotype disorder risk early onset environmental chemical environmental chemical exposure exposed human population gene product in vivo member motor impairment mouse model nervous system disorder oxidative damage pathogenic fungus pollutant postnatal postnatal period prenatal exposure prevent tool

项目摘要

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.

项目概要三核苷酸重复疾病是一类由 DNA 重复变化定义的神经系统疾病。三核苷酸重复疾病，包括亨廷顿病（HD），一种罕见且致命的神经退行性疾病， HD 是由亨廷顿蛋白 (HTT) 中 CAG 三核苷酸序列的重复扩展引起的。基因的扩展超过 36 个 CAG 重复会导致致病性转录物和蛋白质，从而导致晚期疾病。神经退行性变的开始，但严重且终末的形式。整个 CAG 重复序列的长度。基因组不稳定，具有很高的跨代扩展潜力，而 HD 大部分是遗传性的，只有一小部分是遗传性的。部分病例是由于 CAG 重复的零星扩展而产生的，大约 60% 的方差是这样产生的。 HD 症状的发生归因于一个人携带更多的 CAG 重复序列；超过一半的剩余变异与症状发作持续时间有关。归因于尚未发现的环境因素。环境化学物质暴露可能会造成损害。归因于重复不稳定和随后的、散发性的三核苷酸重复疾病，例如HD。事实上，化学诱导的氧化应激会导致 CAG 重复扩增突变。抑制线粒体的杀虫剂会引起小鼠神经元的氧化应激并引发基因表达信号 HD 的性质之一是吡唑醚菌酯，在食品中以非常高的浓度施用以抑制 HD 的性质。预测的人类接触水平表明它们足以抑制人类线粒体。因此，dria 可能会增加 HD 疾病的风险和严重程度。我们的初步结果表明，唑菌胺酯会导致培养细胞中的 CAG 重复扩增我们将检验唑菌胺酯的假设。加速HD的进程，但也能够在非携带者中产生新的致病性重复扩增我们将应用一系列不同的分子、组织病理学和行为工具来表征 HD。广泛接受的 HD 小鼠模型在整个生命过程中暴露于唑菌胺酯的表型。结果将为制定针对有三重疾病家族风险的人的预防战略提供必要的基础此外，我们的工作重新定义了环境化学物质作为诱变剂的作用。扩大了他们作为典型遗传疾病贡献者的作用。