APE1 and Somatic Expansion in Huntington's Disease

摘要 亨廷顿病(HD)是一种破坏性的神经系统疾病，目前尚无药物干预方法 但仍可治愈这种疾病。HD是由亨廷顿蛋白(HTT)基因突变引起的，该基因由一种 扩大CAG重复。HD患者出现症状的年龄差异很大，尽管 致病性CAG重复序列的长度与发病年龄、重复序列长度相等的个体相关 在平均发病年龄几十年后出现各种症状。这一观察结果表明，有 CAG重复长度以外的其他因素可以改变HD症状的发展，提供 制定干预措施以延缓疾病发病的其他替代办法。有趣的是，基因涉及 在DNA修复中已被确定为潜在的影响发病年龄的遗传修饰因素。一位这样的候选人 是与线粒体修复相关的主要哺乳动物脱嘌呤/脱嘧啶核酸内切酶APE1 DNA(MtDNA)损伤，我们已经证明这是导致mt功能障碍、运动丧失的突发性事件 HD的功能和神经退行性变。扩增的CAG重复序列在躯体上是不稳定的，发生在 修复氧化DNA损伤的过程。我们和其他人已经阐明了APE1和 突变型HTT(MHTT)定位于mT并降低HD中mT功能，但我们对APE1如何可能 导致HD患者起病晚，至今仍不完全。我们建议，通过防止线粒体DNA损伤 和躯体扩张，APE1可能是一种遗传修饰物，有助于延缓HD的发病年龄。为了测试 我们的假设是，我们将研究APE1修复活动是否与躯体扩张和发病年龄有关，通过 导致DNA氧化损伤和线粒体功能障碍。建议的研究特别是 与人类健康相关，因为它将提供对APE1和突变的HTT机制功能的前所未有的看法 潜在的HD发病年龄，并增加APE1的调节作为HD未来药物发现的一种机制。

ABSTRACT Huntington’s disease (HD) is a devastating neurological disease to which no pharmacological interventions are yet available to cure the disease. HD is caused by a mutation in the huntingtin (HTT) gene consisting of an expanded CAG repeat. The age at which HD patients develop symptoms is considerably variable and although the length of the pathogenic CAG repeat correlates with age of onset, individuals with equal repeat length develop symptoms various decades after the average age of onset. This observation suggests that there are other factors beyond the CAG repeat length that can modify the development of HD symptoms, providing additional alternatives for the development of interventions to delay disease onset. Interestingly, genes involved in DNA repair have been identified as potential genetic modifiers that influence age of onset. One such candidate is APE1, the major mammalian apurinic/apyrimidinic endonuclease associated with the repair of mitochondrial DNA (mtDNA) damage, which we have shown to be a precipitating event leading to mt dysfunction, loss of motor function and neurodegeneration in HD. The expanded CAG repeat is somatically unstable and occurs during the process of repairing oxidative DNA damage. We and others have elucidated important details for APE1 and mutant HTT (mHTT) that localize to mt and reduces mt function in HD, yet our knowledge of how APE1 may contribute to the late onset in HD patients, remains incomplete. We propose that, by preventing mtDNA damage and somatic expansion, APE1 may be a genetic modifier that contributes to slowing HD age of onset. To test our hypothesis, we will study if APE1 repair activity is implicated in somatic expansion and age of onset by contributing to oxidative DNA damage and mitochondrial dysfunction. The proposed research is particularly relevant to human health, as it will deliver an unprecedented view of APE1 and mutant HTT mechanistic functions underlying HD age of onset and add the regulation of APE1 as a mechanism for future drug discovery in HD.