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.

项目摘要/摘要 睡眠功能障碍是神经退行性疾病中的常见特征，而流行病学研究 强烈表明睡眠破坏和慢性短睡眠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与睡眠之间存在双向关系 失调，但是对将它们绑在一起的机制几乎没有理解。鉴于 建模零星疾病的难度，研究定义模型系统中的现象可能会散发出新的 深入了解这个知识的领域。亨廷顿氏病（HD），这是一个遗传性，完全渗透的，进步的 神经退行性疾病，具有更普遍的神经退行性疾病共同的特征， 例如异常的蛋白质积累，早期认知变化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症状三合会而闻名，较少 高清的已知特征是昼夜节律和睡眠障碍的早期发作。据报道 对于88％ 有助于患者福祉的重要因素。此外，鼠标捕获的鼠标模型兼有 昼夜节律和睡眠障碍。这些数据一起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。鉴于突变体的作用很好 亨廷顿（HTT）在蛋白质稳态破坏时，我们假设蛋白质扰动 稳态破坏了睡眠的神经回路，并且长时间的睡眠功能障碍也相互互动 破坏蛋白质稳态。 自噬适配器蛋白ALFY是聚集突变体HTT的周转所必需的。我们在场 初步数据表明，ALFY水平升高延迟了聚集蛋白在 纹状体，并延迟了两种HD小鼠模型中摩托车功能障碍的发作。同样，我们表明 由于过度表达，在HD小鼠中观察到的睡眠障碍也可能会减少。在AIM1中，我们将 在ALFY表达，神经病理学结局和睡眠行为之间进行相关分析 提高ALFY水平的假设延迟了与睡眠相关的大脑中聚集的突变体HTT的出现 区域又将延迟睡眠障碍的发作。在AIM 2中，我们将应用慢性睡眠剥夺 在预抑制高清小鼠中，测试睡眠功能障碍可能会降低蛋白质稳态和 通过自噬途径加速疾病进展。我们将确定睡眠不足的影响 突变的HTT积累和运动功能障碍。然后，我们将在高清小鼠中过表达Alfy，并测试是否可以 延迟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执行RNA-Seq 慢性睡眠引起的转录变化的更完整表征的区域 剥夺，特别是专注于维持蛋白质稳态的途径。