Cell Signaling Dysregulation in Huntington's Disease

亨廷顿病中的细胞信号传导失调

基本信息

批准号：
10536659
负责人：
Rocio Gomez-Pastor
金额：
$ 33.91万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10536659
关键词：
Address Affect Behavioral Binding Sites Biochemical Brain Brain region CAG repeat Cell Survival Cell model Cells Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Data Degradation Pathway Dependence Dependovirus Disease Disease Progression Energy Metabolism Exhibits Functional disorder Future Gene Expression Genes Genetic Transcription Goals Heat Losses Huntington Disease Huntington gene Impaired cognition Injections Intervention Knock-out Knockout Mice Mediating Mitochondria Molecular Molecular Chaperones Motor Mus Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nucleic Acid Regulatory Sequences Pathologic Pathology Pathway interactions Patients Predisposition Process Protein Kinase Proteins Role Satellite Viruses Signal Transduction Stress Symptoms TP53 gene Tamoxifen Testing Therapeutic Time Transgenic Mice Transgenic Organisms United States Up-Regulation biological adaptation to stress cell type genetic manipulation heat shock transcription factor improved improved outcome mitochondrial dysfunction mouse model mutant neuron loss neuropathology pharmacologic prevent programs protein aggregation restoration small hairpin RNA spatiotemporal synergism therapeutic target transcription factor transcriptome sequencing ubiquitin-protein ligase

项目摘要

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.

亨廷顿氏病（HD）是一种毁灭性的神经退行性疾病（ND），影响约30,000 美国的患者，没有治疗的患者。 HD的特征是大蛋白聚集，优先影响纹状体中的培养基神经元（MSN）。尽管进行了许多研究解决MSN变性在HD病理学中的重要性，对分子知之甚少突变亨廷顿蛋白（MHTT）蛋白通过HD诱导MSN死亡的机制。最近的证据表明，基本热激转录因子1（HSF1）负责应激保护蛋白的表达在HD中的MSN中不当降解。我们假设这一点 HSF1降解是MSN功能障碍和HD损失的关键途径，并防止其退化可能构成一种潜在的理论方法。该提议的目的是表征导致MSN中HSF1降解的机制，即使在高清症状的发作会改善预后。在AIM 1中，我们将检验以下假设，即不合适蛋白质p53在MSN中的积累控制HSF1降解组件的表达途径（蛋白激酶CK2α'和E3连接酶FBXW7），最终导致HSF1和HD损失症状。由于CAG躯体的增强，该途径将优先在MSN中激活在纹状体中观察到不稳定。为了检验该假设，我们将使用分子，药物和遗传原发性神经元和转基因高清小鼠的操作。预期的结果将揭示机制 MSN在HD中发挥功能失调，并为对偏好的未来理解建立基础 MSN对MHTT的敏感性。几项研究试图将HSF1物理激活作为HD的治疗方法，但它们是无法实现长期利益。我们建议防止HSF1降解可能更有效和持久的治疗策略。在AIM 2中，我们将使用药物和遗传操作 HD小鼠中的CK2α’可防止疾病进展过程中不同时间点HSF1降解。这些研究将揭示预防HSF1降解以改善HD症状的时间表并巩固CK2α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，我们在HD中的研究可能鉴定出常见的HSF1 适用于其他ND的降解机制和治疗靶标。