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

• 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
• 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

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.

项目总结/摘要 睡眠障碍是神经退行性疾病的常见特征，而流行病学研究表明， 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。 这些观察结果表明神经退行性事件和睡眠之间存在双向关系 然而，人们对将它们联系在一起的机制知之甚少。鉴于 由于难以对偶发性疾病进行建模，在定义的模型系统中研究这种现象可能会产生新的 深入了解这个未被研究的领域亨廷顿氏病（HD）是一种遗传性、完全渗透性、进行性 神经退行性疾病，具有更普遍的神经退行性疾病的共同特征， 例如异常蛋白质积累、早期认知改变和细胞类型特异性变性。虽然 以运动、认知和精神症状为特征的三联征而闻名， HD已知特征是昼夜节律和睡眠障碍的早期发作。据报道， 到88%的患者承认有睡眠问题，62%的患者认为睡眠问题是“非常”或“中度”的。 影响患者健康的重要因素。此外，高清鼠标模型可以捕捉到 昼夜节律和睡眠障碍。总之，这些数据表明，调节睡眠的神经回路 特别容易受到与HD相关的遗传变化的影响。考虑到突变体的重要作用 亨廷顿蛋白（Htt）在蛋白质稳态的破坏，我们假设，蛋白质的扰动， 内环境平衡破坏了睡眠的神经回路，长期的睡眠功能障碍也会导致睡眠障碍。 破坏了蛋白质的体内平衡 自噬衔接蛋白Alfy是聚集突变体Htt周转所必需的。我们提出 初步数据表明，Alfy水平的增加延迟了聚集蛋白的积累， 纹状体，并在两种HD小鼠模型中延迟运动功能障碍的发作。同样，我们表明， 在HD小鼠中观察到的睡眠障碍也可能由于Alfy过表达而减少。在AIM 1中，我们将 将Alfy表达与神经病理结果和睡眠行为进行相关性分析， 假设增加Alfy水平延迟了睡眠相关脑中聚集突变Htt的出现， 这反过来又会延迟睡眠障碍的发作。在目标2中，我们将应用慢性睡眠剥夺 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。我们将研究睡眠不足如何影响 突变型Htt积累和运动功能障碍。然后，我们将在HD小鼠中过表达Alfy，并测试它是否能 延缓SD诱导的行为和神经病理学变化。最后，我们将在受影响的大脑中进行RNA-seq 区域，以获得慢性睡眠引起的转录变化的更完整的表征 剥夺，特别关注维持蛋白质稳态的途径。