Investigating polyamines as a treatment target for mitochondrial disease

线粒体疾病是一组遗传性疾病，会对人体细胞和组织造成损害，在英国，每4300人中就有一人受到影响。目前还没有获得许可的治疗方法，开发线粒体疾病的治疗策略已被强调为优先领域。线粒体是细胞内的微小结构，在细胞能量产生和新陈代谢中起着关键作用。当这些“动力装置”发生故障时，可能会导致慢性疾病。代谢需求高的器官往往是受影响最严重的，线粒体疾病经常会对神经系统造成损害。来自动物和临床研究的广泛证据也表明，线粒体缺陷在其他神经退行性疾病中发挥着关键作用，包括阿尔茨海默氏症和帕金森氏病。在这个项目中，我们将研究线粒体缺陷如何触发关键代谢基因表达的变化，以及这如何导致神经退化。我们假设大脑中称为多胺的代谢物水平的变化会导致线粒体疾病的神经退化。我们将使用患有线粒体疾病Leigh综合征的果蝇和小鼠来验证这一假设，Leigh综合征会导致儿童神经退化和死亡。我们将使用这些‘疾病模型’来更好地了解疾病的原因，并确定新的治疗方法。苍蝇模型研究速度快，成本低，而小鼠模型更接近于反映人类线粒体疾病。使用高度敏感的技术，我们将测量线粒体如何在Leigh综合征的这个苍蝇模型中引起大脑中多胺代谢物水平的变化。利用尖端基因技术，我们将在苍蝇模型中研究在错误时间开启或关闭的关键代谢基因在神经细胞中的作用，以发现它们是如何导致神经细胞损伤的。我们还将测试阻断关键代谢基因或使用一种名为亚精胺的代谢物治疗是否可以防止对神经系统的损害。总体而言，该项目将导致对线粒体疾病原因的新理解，以及治疗患者这种疾病的新策略。从长远来看，该项目还将有助于了解和治疗其他神经退行性疾病，如阿尔茨海默氏症和帕金森氏症。

Mitochondrial diseases are a group of genetic disorders that cause damage to cells and tissues in the body and affect up to 1 in 4300 people in the UK. There are currently no licenced treatments and developing therapeutic strategies for mitochondrial diseases has been highlighted as a priority area. Mitochondria are tiny structures within cells, which play a critical role in cellular energy production and metabolism. When these 'powerhouses' malfunction, it can result in chronic illness. Organs with high metabolic demands are often the most severely affected and mitochondrial diseases frequently cause damage to the nervous system. Extensive evidence from animal and clinical studies also suggests that defective mitochondria play a critical role in other neurodegenerative diseases, including Alzheimer's and Parkinson's disease. In this project we will study how defective mitochondria trigger changes in the expression of key metabolic genes and how this causes neurodegeneration. We hypothesise that changes in the levels of metabolites called polyamines in the brain contribute to neurodegeneration in mitochondrial disease.We will test this hypothesis using fruit flies and mice that have been given the mitochondrial disease Leigh syndrome, which causes neurodegeneration and death in children. We will use these 'disease models' to better understand the cause of the disease and identify new treatments. The fly model is fast and inexpensive to study, while the mouse model more closely mirrors human mitochondrial disease. Using highly sensitive techniques, we will measure how mitochondria cause changes in polyamine metabolite levels in the brain in this fly model of Leigh syndrome. Using cutting-edge genetic technology, we will study the role of key metabolic genes that are switched on or off at the wrong time in nerve cells in the fly model, to discover how they contribute to nerve cell damage. We will also test whether blocking key metabolic genes, or treatment with a metabolite called spermidine, can prevent damage to the nervous system. Overall, this project will lead to a new understanding of the cause of mitochondrial disease and novel strategies to treat the disease in patients. In the long-term the project will also contribute to the understanding and treatment of other neurodegenerative diseases such as Alzheimer's and Parkinson's disease.