Understanding the Relationship Between Protein Homeostasis and Sleep Dysfunction in Mouse Models of Huntington's Disease

了解亨廷顿病小鼠模型中蛋白质稳态与睡眠障碍之间的关系

基本信息

批准号：
10593596
负责人：
Yueqing Peng
金额：
$ 45.24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-27 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593596
关键词：
Adaptor Signaling Protein Adult Affect Appearance Area Autophagocytosis Behavioral Biological Models Brain Brain Stem Brain region Cell Nucleus Chronic Circadian Rhythms Clinical Corpus striatum structure Data Disease Disease Progression Event Foundations Future Genetic Genetic Transcription Health Heritability Huntington Disease Huntington gene Hypothalamic structure Inherited Knock-in Link Modeling Movement Mus Mutation Nerve Degeneration Neurobehavioral Manifestations Neurodegenerative Disorders Onset of illness Outcome Pathogenicity Pathway interactions Patients Personal Satisfaction Physiological Proteins Regimen Reporting Risk Factors Role Sleep Sleep Deprivation Sleep Disorders Sleep disturbances Symptoms Testing Triad Acrylic Resin Work base cell type cognitive change early onset epidemiology study insight member motor disorder mouse model mutant neural circuit overexpression protein aggregation proteostasis psychiatric symptom single-cell RNA sequencing sleep behavior sleep onset transcriptome sequencing

项目摘要

Project Summary/Abstract Sleep dysfunction is a common feature in neurodegenerative diseases, whereas epidemiologic studies strongly suggest that sleep disruption and chronic short sleep may also be risk factors for the onset of disease. These observations suggest a bidirectional relationship between neurodegenerative events and sleep dysregulation, however there is little understanding about the mechanisms that tie them together. Given the difficulty with modeling sporadic disorders, studying the phenomenon in a defined model system may shed new insight into this understudied area. Huntington’s disease (HD), which is a hereditary, fully penetrant, progressive neurodegenerative disorder, shares features that are common to more prevalent neurodegenerative diseases, such as abnormal protein accumulation, early cognitive changes, and cell type specific degeneration. Although known for the triad of symptoms characterized by movement, cognitive and psychiatric symptoms, a lesser known feature of HD is an early onset of circadian rhythm and sleep disturbances. It has been reported that up to 88% of patients acknowledge having sleep problems, which were rated by 62% as either “very” or “moderately” important factors contributing towards the patient well-being. Moreover, mouse models of HD capture both circadian rhythm and sleep disturbances. Together, these data suggest that the neural circuitry regulating sleep is especially vulnerable to the genetic changes associated with HD. Given the well appreciated role of mutant Huntingtin (Htt) in the disruption of protein homeostasis, we hypothesize that perturbations in protein homeostasis disrupts the neural circuitry underlying sleep, and that prolonged sleep dysfunction also reciprocally disrupts protein homeostasis. The autophagy adaptor protein Alfy is required for the turnover of aggregated mutant Htt. We present preliminary data demonstrating that increased levels of Alfy delays the accumulation of aggregated protein in the striatum, and delays the onset of motoric dysfunction in two mouse models of HD. Similarly, we show that sleep disturbances observed in HD mice may also be diminished due to Alfy over-expression. In Aim1, we will perform correlative analyses between Alfy expression, neuropathological outcomes and sleep behavior to test the hypothesis that increasing Alfy levels delays the appearance of aggregated mutant Htt in sleep-related brain regions, which in turn will delay the onset of sleep disturbances. In Aim 2, we will apply chronic sleep deprivation in presymptomatic HD mice to test the hypothesis that sleep dysfunction may decrease protein homeostasis and accelerate disease progression via the autophagy pathway. We will determine how sleep deprivation impacts mutant Htt accumulation and motor dysfunction. Then, we will overexpress Alfy in HD mice and test if it can delay SD-induced behavioral and neuropathological changes. Finally, we will perform RNA-seq in affected brain regions to acquire a more complete characterization of the transcriptional changes evoked by chronic sleep deprivation, particularly focusing on pathways that maintain protein homeostasis.

项目概要/摘要睡眠障碍是神经退行性疾病的一个常见特征，而流行病学研究强烈表明睡眠中断和长期睡眠不足也可能是疾病发作的危险因素。这些观察表明神经退行性事件和睡眠之间存在双向关系失调，然而，人们对将它们联系在一起的机制知之甚少。难以对散发性疾病进行建模，在定义的模型系统中研究该现象可能会产生新的结果深入了解这一尚未被研究的领域，这是一种遗传性、完全渗透性、进行性的疾病。神经退行性疾病，具有更流行的神经退行性疾病的共同特征，例如异常蛋白质积累、早期认知变化和细胞类型特异性退化。以运动、认知和精神症状为特征的三联征，较轻的 HD的已知特征是早发性昼夜节律和睡眠障碍。据报道。 88% 的患者承认有睡眠问题，62% 的患者将其评为“非常”或“中度” 此外，HD 小鼠模型同时捕获了这两个因素。昼夜节律和睡眠障碍一起，这些数据表明调节睡眠的神经回路。鉴于突变体的作用已得到广泛认可，因此特别容易受到与 HD 相关的遗传变化的影响。亨廷顿蛋白 (Htt) 破坏蛋白质稳态，我们捕获了蛋白质中的扰动体内平衡会破坏睡眠的神经回路，而长期的睡眠功能障碍也会反过来影响睡眠的神经回路。破坏蛋白质稳态。我们提出了自噬衔接蛋白 Alfy 是聚集突变体 Htt 周转所需的。初步数据表明，增加 Alfy 水平可延迟体内聚集蛋白的积累纹状体，并延迟了两种 HD 小鼠模型的运动功能障碍的发生。类似地，我们证明了这一点。在 HD 小鼠中观察到的睡眠障碍也可能因 Alfy 过度表达而减少。对 Alfy 表达、神经病理结果和睡眠行为之间进行相关分析以进行测试假设增加 Alfy 水平会延迟睡眠相关大脑中聚集突变体 Htt 的出现区域，这反过来会延迟睡眠障碍的发生。在目标 2 中，我们将采用慢性睡眠剥夺。在症状前 HD 小鼠中测试睡眠功能障碍可能降低蛋白质稳态的假设通过自噬途径加速疾病进展我们将确定睡眠剥夺如何影响。然后，我们将在HD小鼠中过度表达Alfy并测试是否可以。延迟 SD 引起的行为和神经病理变化最后，我们将在受影响的大脑中进行 RNA 测序。区域以获得长期睡眠引起的转录变化的更完整特征剥夺，特别关注维持蛋白质稳态的途径。