Age of Onset and Huntingtons Disease

由于老年人口的空前增加，与年龄有关的疾病预计将增加 在未来几年呈指数增长。其中，神经退行性疾病将是最具破坏性的， 他们的情绪和经济影响。未来十年，至少有2%的美国人将受到折磨 患有某种形式的阿尔茨海默病（AD）（4，000，000），帕金森病（PD）（1，500，000），或 亨廷顿氏病（HD）（200，000）等。这些疾病中的每一种都会影响患者数十年， 然而，目前还没有有效的长期治疗方法。在本提案中，我们旨在测试 预防或延迟HD发作和进展的机制。我们惊奇地发现， 氧化损伤导致亨廷顿氏病的体细胞扩张， 控制着中年左右的发病单碱基切除修复酶8-氧代鸟嘌呤缺失 糖基化酶（OGG 1），在hHD/OGG 1（-/-）小鼠中停止CAG三联体重复的年龄依赖性扩增， 在MHTT小鼠中观察到。第二个令人惊讶的是，扩张的损失伴随着一个不可预见的 病理生理学的改善（或至少显著延迟）。表达hHD蛋白但缺乏 OGG 1似乎没有在这些动物的生命后期通常观察到的可见疾病体征。 这些数据第一次证明了意外的发现，DNA碱基的氧化和/或其 去除是DNA扩增和毒性发作的致病因素。我们发现， OGG 1停止扩增提供了氧化DNA损伤和DNA损伤机制之间的直接分子联系。 扩张和病理生理学的开始。我们已经创建了一个新的高清鼠标模型，其中mhtexpressing 将150个重复的动物（HD 150 KI）与缺乏OGG 1（-/-）产生的动物杂交 （HD 150 KI/OGG 1（-/-））后代。HD 150 KI动物表现出神经学表型，传递扩展的 等位基因，并扩大体细胞组织中的遗传等位基因随着年龄的增长。相比之下，HD 150 KI/OGG 1（-/-）动物可 遗传CAG重复，但不能在体脑细胞中扩展其重复。两种小鼠均表达mhtt。因为， OGG 1（-/-）动物本身没有可观察到的神经学表型，HD 150 KI/OGG 1（-/-）小鼠 将使我们能够测试相对于他们的mht表达，体细胞扩张的丧失是否改变疾病的发作。 对应物（HD 150 KI）。我们的模型预测，抑制躯体扩张将抵消或延迟发病 运动功能障碍和其他疾病病理生理学指标的研究 HD 150 KI动物。我们还将测试OGG 1活性是否是体细胞扩增和 与疾病发作相关的外周生物标志物升高。我们将测试是否减少体细胞 在HD 150 KI/OGG 1（-/-）小鼠中观察到的扩增伴随着生物标志物相对于 HD 150 KI动物。在相反的方法中，我们将通过治疗减少HD 150 KI小鼠中生物标志物的产生。 与抗氧化剂，并测试是否体细胞扩张也减少。

Due to unprecedented increases in the elderly populations, age-related diseases are expected to increase exponentially in the coming years. Among these, neurodegenerative diseases will be the most devastating in terms of their emotional and economic effects. In the next decade, at least 2% of Americans will be afflicted with some form of Alzheimer’s disease (AD) (4,000,000), Parkinson’s disease (PD) (1,500,000), or Huntington’s disease (HD) (200,000), among others. Each of these disorders can affect patients for decades, yet no effective long-term approaches to therapy are currently available. In this proposal, we aim to test mechanisms that prevent or delay onset of and progression of HD. We have surprisingly found that a DNA oxidative damage causes the somatic expansion in Huntington’s Disease that is observed with age and governs onset that begins around mid-life. Loss of a single base excision repair enzyme, 8-oxo-guanine glycosylase (OGG1), in hHD/OGG1(-/-) mice stops age-dependent expansion of CAG triplet repeats that is observed in mhtt mice. A second surprise was that loss of expansion was accompanied by an unforeseen amelioration (or at least a substantial delay) of pathophysiology. Animals expressing hHD protein but lacking OGG1 appeared devoid of visible signs of disease typically observed late in the lifetime of these animals. These data demonstrate, for the first time, the unexpected finding that oxidation of DNA bases and/or their removal are causative factors in both DNA expansion and the onset of toxicity. Our discovery that loss of OGG1 stops expansion provides a direct molecular link between oxidative DNA damage and the mechanism of expansion, and onset of pathophysiology. We have created a new HD mouse model in which an mhttexpressing animal of 150 repeats (HD150KI) is crossed with an animals lacking OGG1(-/-) producing (HD150KI/OGG1(-/-)) progeny. HD150KI animals display a neurological phenotype, transmit an expanded allele, and expand the inherited allele in somatic tissues with age. In contrast, HD150KI/OGG1(-/-) animals can inherit the CAG repeat but cannot expand their repeats in somatic brain cells. Both mice express mhtt. Since, the OGG1(-/-) animals have no observable neurological phenotype on their own, the HD150 KI/OGG1(-/-) mice will allow us to test whether loss of somatic expansion alters disease onset relative to their mhtt-expressing counterparts (HD150KI). Our model predicts that suppressing somatic expansion will offset or delay the onset of motor dysfunction and other measures of disease pathophysiology in HD150 KI/OGG1(-/-) mice relative to HD150KI animals. We will also test whether OGG1 activity is the source of both the somatic expansion and rise in the peripheral biomarkers associated with disease onset. We will test whether reduction in somatic expansion observed in HD150 KI/OGG1(-/-) mice is accompanied by reduction in the biomarker relative to HD150KI animals. In a reverse approach, we will reduce biomarker production in HD150KI mice by treatment with anti-oxidants, and test whether somatic expansion is also reduced.