Mitochondrial DNA and Ape1 in Huntington's Disease

 描述（由申请方提供）：大量证据表明，氧化应激和线粒体功能障碍可能在HD相关神经变性中发挥作用。然而，突变型亨廷顿蛋白（htt）引起线粒体功能障碍的确切机制在很大程度上仍不清楚。我们最近证明了Ape 1，主要的哺乳动物脱嘌呤/脱嘧啶（AP）核酸内切酶，参与碱基切除修复（BER）途径，对线粒体功能的调节作用。因此，我们的主要目标是确定突变htt背景下Ape 1介导的线粒体功能障碍的机制。该提案将检验突变htt与年龄相关效应相结合，通过靶向Ape 1介导线粒体功能障碍和神经变性，从而导致mtDNA修复缺陷的假设。我们建议使用HD的体内和体外模型的组合来测试我们的假设，并通过确定以下因素来直接测试我们的假设：1）Ape 1突触神经末梢的年龄相关变化是否有助于HD中的mtDNA损伤，线粒体功能障碍和神经退行性变; 2）在htt突变的背景下，什么机制可能触发Ape 1相关的线粒体功能障碍。本研究可能为Ape 1在突变型ht诱导的mt功能障碍和神经退行性变中的可能调控机制提供见解。

 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.