Investigation of Heat shock Factor 1 as a Therapeutic Target for Huntington s Disease

在发达国家，预期寿命的增加导致了与年龄相关的神经退行性疾病（如阿尔茨海默病）的发病率增加。s病和帕金森？这种疾病已经给家庭、社区和整个国家造成了重大的健康、社会和经济负担。通过对罕见的阿尔茨海默病遗传形式的研究，对这些疾病的病因有了深入的了解。s和帕金森？还有遗传性疾病，比如亨廷顿舞蹈症。年代的疾病。潜在的突变导致与疾病相关的蛋白质错误折叠并采用异常形状，从而使它们以有害的方式与自身或其他蛋白质相互作用。这些异常的相互作用导致脑细胞的功能障碍和死亡。减缓或停止这些蛋白质折叠进程的治疗方法疾病并不存在。所有的细胞都必须确保每一种蛋白质都被折叠成正确的形状或构象。细胞使用伴侣？为了折叠蛋白质，如果这一再失败，错误折叠的蛋白质被分解或降解。如果这种去除错误折叠蛋白质的自然过程受到抑制，比如存在与疾病相关的易于聚集的蛋白质，错误折叠的蛋白质就会积聚并聚集在一起，形成蛋白质聚集体。细胞维持正确折叠蛋白质的能力随着年龄的增长而减弱，导致老年人对蛋白质折叠疾病的易感性增加。可能降低聚集倾向蛋白错误折叠倾向的策略包括增加细胞的蛋白质折叠或蛋白质降解能力。一种可能的方法是利用这些细胞？对导致蛋白质错误折叠的损伤的天然防御，例如热或有毒化学物质。这个吗?热休克反应？导致许多被称为热休克蛋白的伴侣蛋白水平立即增加，并由热休克因子1 （HSF1）启动。我们最近获得了一种药物，它可以穿过血脑屏障，激活脑细胞中的HSF1。我们也在建立小鼠模型，我们可以在大脑中诱导HSF1激活形式的存在。我们将使用这些互补的方法来理解脑细胞中的热休克反应，并在亨廷顿舞蹈症小鼠模型中测试HSF1的激活是否可以减轻疾病相关表型。年代的疾病。这项工作将使我们能够确定是否应该将HSF1的激活作为亨廷顿舞蹈症治疗发展的目标。S疾病和其他神经退行性疾病。

Increased life expectancy in the developed world has resulted in a greater incidence of age-related neurodegenerative disorders such as Alzheimer?s disease and Parkinson?s disease, which already impose a significant health, social and economic burden on families, communities and the country as a whole. Insight into the cause of these diseases has arisen through the study of rare genetic forms of Alzheimer?s and Parkinson?s disease as well as from inherited disorders like Huntington?s disease. The underlying mutations cause disease related proteins to misfold and adopt abnormal shapes allowing them to interact with themselves or other proteins in a detrimental manner. These aberrant interactions result in the malfunction and death of brain cells. Treatments that will slow or halt the progression of these ?protein-folding? diseases do not exist. All cells must ensure that as every protein is made, it is folded into the correct shape or conformation. Cells use ?chaperones? to fold proteins and if this is repeatedly unsuccessful, misfolded proteins are broken down or degraded. If this natural process to remove misfolded proteins becomes overwhelmed, as in the presence of a disease-related aggregation-prone protein, misfolded proteins accumulate and clump together as protein aggregates. The capacity of cells to maintain correctly folded proteins diminishes with age, resulting in an increasing susceptibility to protein-folding disease in the elderly. Strategies that might decrease the propensity of an aggregation-prone protein to misfold include increasing either the protein folding or protein degradation capacity of the cell. One possible approach is to harness the cells? natural defence against insults that cause proteins to misfold e.g. heat or toxic chemicals. This ?heat shock response? leads to the immediate increase in levels of many chaperones known as heat shock proteins and is switched on by heat shock factor 1 (HSF1). We have recently gained access to a drug that can cross the blood brain barrier and activate HSF1 in brain cells. We are also generating mouse models in which we can induce the presence of an activated form of HSF1 in brain. We shall use these complementary approaches understand the heat shock response in brain cells and to test whether activation of HSF1 can alleviate disease-related phenotypes in a mouse model of Huntington?s disease. This work will allow us to determine whether the activation of HSF1 should be pursued as a target for therapeutic development for Huntington?s disease and other neurodegenerative disorders.