Cell Signaling Dysregulation in Huntington's Disease

亨廷顿氏病（HD）是一种破坏性的神经退行性疾病（ND），影响约30，000 美国患者，且无可用治疗。HD的特征是大量蛋白质 聚集，优先影响纹状体中的中型棘神经元（MSN）。尽管有许多研究 虽然在HD病理学中阐明了MSN变性的重要性，但关于MSN变性的分子机制知之甚少。 突变亨廷顿蛋白（mHTT）诱导HD MSN死亡的机制。 最近的证据表明，必需的热休克转录因子1（HSF 1），负责 应激保护蛋白的表达在HD的MSN中被不适当地降解。我们假设 HSF 1降解是参与HD中MSN功能障碍和丧失的关键途径， 降解可以构成潜在的治疗方法。本提案的目标是描述 导致MSN中HSF 1降解的机制，并确定即使在 HD症状的发作导致改善的结果。在目标1中，我们将测试不适当的假设， MSN中p53蛋白的积累控制HSF 1降解组分的表达 途径（蛋白激酶CK2α'和E3连接酶Fbxw7），最终导致HSF 1和HD的丧失。 生物学。由于增强的CAG体细胞信号转导，该通路将在MSN中优先激活。 在纹状体中观察到不稳定性。为了验证这一假设，我们将使用分子，药理学和遗传学 在原代神经元和转基因HD小鼠中的操作。预期结果将揭示机制 由此MSN在HD中变得功能失调，并为未来理解首选的 MSN对mHTT的易感性。 几项研究试图将HSF 1作为HD的治疗方法，但它们 未能实现长期效益。我们认为，防止HSF 1降解可能是一种更有效的方法， 和持久的治疗策略。在目标2中，我们将使用药理学和遗传操作， CK 2 α'在HD小鼠中的作用，以防止疾病进展期间不同时间点的HSF 1降解。这些 研究将揭示防止HSF 1降解对改善HD症状是必要的时间范围 进一步证实了CK 2 α'作为HD潜在的治疗靶点。HSF 1、p53和CK2的变化也是 在其他神经退行性疾病中观察到，因此，我们在HD中的研究可能会发现常见的HSF 1 降解机制和治疗目标适用于其他ND。

Huntington’s disease (HD) is a devastating neurodegenerative disease (ND) that affects approximately 30,000 patients in United States and for which no therapies are available. HD is characterized by massive protein aggregation, preferentially affecting medium spiny neurons (MSNs) in the striatum. Despite numerous studies addressing the importance of MSN degeneration in HD pathology, very little is known about the molecular mechanisms by which mutant huntingtin (mHTT) protein induces MSN death in HD. Recent evidence demonstrated that the essential heat shock transcription factor 1 (HSF1), responsible for the expression of stress protective proteins, is inappropriately degraded in MSNs in HD. We hypothesize that HSF1 degradation is a key pathway involved in MSN dysfunction and loss in HD and preventing its degradation may constitute a potential therapeutic approach. The goal of this proposal is to characterize the mechanism that leads to HSF1 degradation in MSNs, and determine if reversal of this process, even after onset of HD symptoms leads to improved outcomes. In Aim 1 we will test the hypothesis that inappropriate accumulation of the protein p53 in MSNs controls the expression of components of the HSF1 degradation pathway (protein kinase CK2α’ and E3 ligase Fbxw7), ultimately leading to loss of HSF1 and HD symptomology. This pathway would be preferentially activated in MSNs due to the enhanced CAG somatic instability observed in the striatum. To test this hypothesis, we will use molecular, pharmacological and genetic manipulations in primary neurons and transgenic HD mice. The expected results will reveal the mechanism/s by which MSNs become dysfunctional in HD and establish the basis for future understanding of the preferred susceptibility of MSNs to mHTT. Several studies have attempted to pharmacologically activate HSF1 as a therapeutic approach in HD, but they failed in achieving long-term benefits. We propose that preventing HSF1 degradation may be a more effective and long-lasting therapeutic strategy. In Aim 2 we will use pharmacological and genetic manipulations of CK2α’ in HD mice to prevent HSF1 degradation at different time points during disease progression. These studies will reveal the timeframe in which preventing HSF1 degradation is necessary to improve HD symptoms and consolidate CK2α’ as a potential therapeutic target for HD. Changes in HSF1, p53 and CK2 are also observed in other neurodegenerative diseases and therefore, our studies in HD may identify common HSF1 degradative mechanisms and therapeutic targets applicable to other NDs.