Cell Signaling Dysregulation in Huntington's Disease

亨廷顿病(HD)是一种毁灭性的神经退行性疾病(ND)，影响约30,000人 在美国，没有治疗方法的患者。HD以大量蛋白质为特征 聚集，优先影响纹状体中的中棘神经元(MSN)。尽管有许多研究 关于MSN变性在HD病理中的重要性，人们对其分子知之甚少 突变的Huntingtin(MHTT)蛋白在HD中诱导MSN死亡的机制。 最近的证据表明，关键的热休克转录因子1(HSF1)，负责 在HD的MSN中，应激保护蛋白的表达被不适当地降解。我们假设 HSF1降解是HD患者MSN功能障碍和丢失及预防其发生的关键途径 降解可能构成一种潜在的治疗方法。这项提案的目标是将 导致MSN中HSF1降解的机制，并确定这一过程是否逆转，即使在 HD症状的出现会改善预后。在目标1中，我们将测试不适当的假设 P53蛋白在MSN中的积累控制HSF1降解成分的表达 途径(蛋白激酶CK2α‘和E3连接酶Fbxw7)，最终导致HSF1和HD的丢失 症状学。由于增强的CAG体细胞，该途径在MSNS中优先被激活 在纹状体观察到不稳定。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/S 从而使MSN在HD中变得功能障碍，并为未来理解首选的 MSN对mHTT的敏感性。 一些研究试图从药物上激活HSF1作为HD的一种治疗方法，但他们 未能实现长期利益。我们建议，防止HSF1降解可能是一种更有效的 和持久的治疗策略。在目标2中，我们将使用药物和遗传操作 在HD小鼠体内的CK2HSF1‘，以防止疾病进展过程中不同时间点的α降解。这些 研究将揭示防止HSF1降解对于改善HD症状是必要的时间框架 巩固CK2α‘作为HD的潜在治疗靶点。HSF1、P53和CK2的变化也是 在其他神经退行性疾病中观察到，因此，我们对HD的研究可能确定常见的HSF1 适用于其他NDS的降解机制和治疗靶点。

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.