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：
10395573
负责人：
Brandon L Pearson
金额：
$ 20.25万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395573
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.

项目摘要三核苷酸重复疾病是由DNA重复变化定义的一类神经系统疾病。许多三核苷酸重复疾病，包括亨廷顿氏病（HD），这是一种罕见而致命的神经退行性疾病，继承。 HD是由Huntingtin（HTT）中CAG三核苷酸序列的重复量扩展引起的基因。大于36个CAG重复的膨胀导致致病转录物和蛋白质导致迟到发作，但神经变性的严重和末端形式。整个CAG重复序列的长度基因组是不稳定的，具有跨几代扩展的高潜力。虽然高清主要是继承的，但很小案例比例是通过零星的CAG重复量零星扩张而产生的。大约60％的差异高清症状的发作归因于一个人携带的CAG数量。更多CAG扩展与早期发作有关。症状发作持续时间的剩余变异性的一半以上具有归因于尚未发现的环境因素。环境化学暴露可能会致敬，重复不稳定性，随后是零星形式的三核苷酸重复疾病，例如HD。在- 契据，化学诱导的氧化应激会导致CAG重复膨胀突变。我们以前证明了线粒体抑制农药会导致小鼠神经元中的氧化应激，并引起基因表达sig- 高清的性质。该农药类别的一位成员是pyraclostrobin，在食物上非常高，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条 - 因此，DRIA可能会导致高清疾病风险和严重程度。我们的初步结果表明乙乳糖蛋白在培养细胞中引起CAG重复膨胀。我们将测试吡咯霉素的假设加速了HD的过程，但也能够在非行动中产生新的致病性重复扩张 ers。我们将应用一组分子，组织病理学和行为工具来表征HD 在整个生命过程中，在pyraclostrobin暴露时，在广泛接受的HD小鼠模型中表型。我们的结果将为家庭风险trinu的人建立预防策略所必需的基础克服重复疾病。此外，我们的工作重新定义了环境化学物质作为诱变剂和扩大了作为规范遗传疾病的贡献者的作用。