Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
PLoS One. 2011;6(11):e27408. doi: 10.1371/journal.pone.0027408. Epub 2011 Nov 7.
DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB) repair, is involved in the pathology of Huntington's disease (HD). Mutant huntingtin (Htt) impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt) in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.
在神经元的漫长寿命中，基因组 DNA 中的 DNA 损伤不断积累，因此 DNA 损伤修复对于保持神经元的正常功能是必不可少的。我们之前报道过，Ku70 是 DNA 双链断裂 (DSB) 修复的关键分子，它参与亨廷顿病 (HD) 的病理学。突变型亨廷顿蛋白 (Htt) 通过直接相互作用损害 Ku70 功能，而 Ku70 的补充恢复了 HD 模型小鼠的表型。在这项研究中，我们通过不同的驱动子在眼睛或运动神经元中表达突变型亨廷顿蛋白 (Htt)，生成了多个果蝇 HD 模型，并显示出各种表型。在这些果蝇模型中，Ku70 的共表达恢复了寿命、运动活性和眼睛退化。相比之下，Ku70 的杂合缺失突变或 siRNA 介导的敲低加速了寿命缩短和运动障碍。这些结果共同表明，Ku70 是 HD 病理学的关键介质，也是 HD 的候选治疗靶点。
