Mitochondrial DNA and Ape1 in Huntington's Disease

 描述(申请人提供)：大量证据表明，氧化应激和线粒体功能障碍可能在与HD相关的神经退行性变中发挥作用。然而，突变的亨廷顿蛋白(HTT)导致线粒体功能障碍的确切机制(S)在很大程度上仍不清楚。我们最近证实了参与碱基切除修复(BER)途径的主要哺乳动物脱嘌呤/脱嘧啶(AP)内切酶APE1对线粒体功能的调节作用。因此，我们的主要目标是在突变型HTT的背景下确定APE1介导的线粒体功能障碍的机制。这项提议将检验这样的假设，即突变的HTT结合年龄相关的效应，通过靶向APE1介导线粒体功能障碍和神经变性，这反过来又导致mtDNA修复不足。我们建议使用体内和体外HD模型来验证我们的假设，并通过确定是否：1)APE1型突触神经末梢的年龄相关变化导致HD患者线粒体DNA损伤、线粒体功能障碍和神经变性，以及2)在HTT突变的背景下，什么机制(S)可能触发APE1型线粒体功能障碍，来直接检验我们的假设。这项研究可能为APE1在突变的HTT诱导的线粒体功能障碍和神经变性中的可能调节机制提供洞察力。

 DESCRIPTION (provided by applicant): Substantial evidence suggests that oxidative stress and mitochondrial dysfunction may play a role in neurodegeneration associated with HD. However, the precise mechanism(s) by which mutant huntingtin (htt) causes mitochondrial dysfunction remain largely unknown. We recently demonstrated a regulatory role of Ape1, the major mammalian apurinic/apyrimidinic (AP) endonuclease that participates in the base excision repair (BER) pathway, on mitochondrial function. Thus, our main objective is to determine the mechanisms of Ape1-mediated mitochondrial dysfunction in the context of mutant htt. This proposal will test the hypothesis that mutant htt, in combination with age-related effects, mediates mitochondrial dysfunction and neurodegeneration by targeting Ape1, which in turn results in deficient repair of mtDNA. We propose to test our hypothesis using a combination of in vivo and in vitro models of HD and directly test our hypothesis by determining if: 1) age-related changes in Ape1 synaptic nerve terminals contribute to mtDNA damage, mitochondrial dysfunction and neurodegeneration in HD and 2) what mechanism(s) might trigger Ape1-associated mitochondrial dysfunction in the context of the htt mutation. This study is likely to provide insight into a possible regulatory mechanism of Ape1 in mutant htt-induced mt dysfunction and neurodegeneration.