APE1 and Somatic Expansion in Huntington's Disease

摘要 亨廷顿氏病（HD）是一种毁灭性的神经系统疾病， 但仍能治愈疾病HD是由亨廷顿蛋白（HTT）基因突变引起的， 扩增CAG重复序列。HD患者出现症状的年龄差异很大， 致病性CAG重复序列的长度与发病年龄相关，重复序列长度相等的个体 在平均发病年龄后几十年才出现症状。这一观察表明， CAG重复序列长度以外的其他因素可以改变HD症状的发展， 制定干预措施以延迟疾病发作的其他替代办法。有趣的是， 在DNA修复已被确定为影响发病年龄的潜在遗传修饰剂。一个这样的候选人 是APE 1，与线粒体损伤修复相关的主要哺乳动物脱嘌呤/脱嘧啶核酸内切酶。 DNA（mtDNA）损伤，我们已经证明这是一个导致mt功能障碍，运动功能丧失的突发事件， 功能和神经退行性变。扩增的CAG重复序列是体细胞不稳定的，发生在 修复氧化DNA损伤的过程。我们和其他人已经阐明了APE 1的重要细节， 突变HTT（mHTT）定位于mt并降低mt在HD中的功能，但我们对APE 1如何 导致HD患者迟发性，仍不完整。我们认为，通过防止线粒体DNA损伤， 和体细胞扩张，APE 1可能是一种遗传修饰剂，有助于减缓HD发病年龄。测试 我们的假设，我们将研究APE 1修复活性是否与体细胞扩张和发病年龄有关， 导致氧化性DNA损伤和线粒体功能障碍。该研究特别是 与人类健康相关，因为它将提供APE 1和突变HTT机制功能的前所未有的观点 基础HD发病年龄，并添加APE 1的调节作为未来HD药物发现的机制。

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.