TARGETING PARKIN & MITOCHONDRIAL DYNAMICS IN HUNTINGTON'S DISEASE

亨廷顿氏病是一种无法治愈的致命性神经退行性疾病，其特征在于患者大脑中脆弱神经元的丧失。这种疾病是由编码亨廷顿蛋白（HTT）基因中氨基酸谷氨酰胺的特定DNA序列（三核苷酸CAG重复序列）的大小增加引起的。如果HTT蛋白中谷氨酰胺的数量增加超过临界长度，它就会错误折叠并形成蛋白质缠结，这可能会破坏重要的细胞过程。HTT基因中CAG重复单位数量的增加与亨廷顿病的早期发病有关。然而，在重复次数相同的个体中，症状的发作存在很大的变异性，研究表明，这种变异的约40%是由于其他基因。这表明，在人类基因组中，有许多潜在的治疗靶点能够显著改变疾病发作的年龄。我们实验室和其他人之前的工作发现，线粒体--细胞的能量发电站--在亨廷顿病中的几个方面功能不正常。有趣的是，我们最近发现，蛋白帕金，这是清除不健康的线粒体细胞的关键，可以改善疾病的症状，在一个果蝇模型的亨廷顿。值得注意的是，编码parkin的基因突变会导致遗传性帕金森病。在这里，我们建议剖析潜在的parkin保护机制。由于parkin参与控制线粒体的形状，我们将使用各种基于显微镜的技术来询问线粒体形态，以查看在亨廷顿的模型苍蝇的背景下parkin是否影响这一过程。同时，我们还将使用几种生化方法研究这些果蝇的线粒体功能。我们还将扩展这项工作，系统地测试与parkin功能和线粒体动力学相关的几种蛋白质，以便更好地了解parkin如何影响亨廷顿果蝇的疾病“症状”。总之，这项工作将告知亨廷顿病的潜在机制，最终可能导致这种疾病的新治疗策略的发展。由于线粒体功能障碍与几种神经退行性疾病有关，任何令人信服的见解最终都可能具有更广泛的意义。

Huntington's disease is an incurable, fatal neurodegenerative disorder that is characterised by the loss of vulnerable neurons in the brains of patients. The disease is caused by an increase in the size of a particular DNA sequence (a trinucleotide CAG repeat) which encodes for the amino acid glutamine in the huntingtin (HTT) gene. If the number of glutamines in the HTT protein increases beyond a critical length it misfolds and forms protein tangles, which can disrupt vital cellular processes. An increased number of CAG repeat units in the HTT gene is associated with an earlier age of Huntington's onset. However, there is substantial variability in the onset of symptoms in individuals with the same number of repeats, and studies have shown that ~40 % of this variation is due to other genes. This suggests that there are many potential therapeutic targets capable of significantly altering age of disease onset in the human genome.Previous work by our laboratory and others has found that mitochondria - the energy powerhouses of cells - do not function properly in several ways in Huntington's disease. Interestingly, we have recently found that the protein parkin, which is critical for clearing unhealthy mitochondria for the cell, can improve disease symptoms in a fruit fly model of Huntington's. Notably, mutations in the gene encoding parkin cause hereditary forms of Parkinson's disease. Here we propose to dissect the mechanisms underlying parkin protection. As parkin is involved in controlling the shape of mitochondria, we will interrogate mitochondrial morphology using various microscopy-based techniques, in order to see if in the context of Huntington's model flies parkin influences this process. In parallel, we will also study mitochondrial function in these flies using several biochemical approaches. We will also extend this work to systematically test several proteins related to parkin function and mitochondrial dynamics, in order to better understand how parkin is influencing disease "symptoms" in Huntington's flies. In total, this work will inform the mechanisms underlying Huntington's disease, will may ultimately lead to the development of novel therapeutic strategies for this disorder. As mitochondrial dysfunction is linked to several neurodegenerative diseases, any compelling insights may ultimately have broader significance.