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 睡眠障碍是神经退行性疾病的共同特征，而流行病学研究 强烈表明，睡眠中断和慢性短睡眠也可能是疾病发病的风险因素。 这些观察表明，神经退行性事件和睡眠之间存在双向关系。 然而，人们对将它们联系在一起的机制知之甚少。给定 对散发性疾病建模的困难，在确定的模型系统中研究这一现象可能会带来新的 洞察这一未被研究的领域。亨廷顿病(HD)是一种遗传性、全透性、进行性的疾病 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， 如蛋白质异常堆积、早期认知改变和细胞类型特异性退化。虽然 以运动、认知和精神症状为特征的三重症状而闻名，较轻的 HD的已知特征是早起的昼夜节律和睡眠障碍。据报道，上个月 至88%的患者承认有睡眠问题，62%的患者认为睡眠问题很严重或不严重。 影响患者健康的重要因素。此外，HD的鼠标模型既能捕捉到 昼夜节律和睡眠障碍。总而言之，这些数据表明调节睡眠的神经回路 尤其容易受到与HD相关的基因变化的影响。鉴于突变体的作用得到了很好的评价 亨廷顿蛋白(Huntingtin，Htt)在破坏蛋白质动态平衡的过程中，我们假设蛋白质存在扰动 动态平衡会扰乱睡眠背后的神经回路，而长期的睡眠功能障碍也会反过来 会破坏蛋白质的动态平衡。 自噬适配蛋白Alfy是聚集突变体Htt周转所必需的。我们呈现的是 初步数据显示，ALFY水平的增加延缓了聚集蛋白在 并延缓两种HD小鼠模型运动功能障碍的发生。类似地，我们表明 在HD小鼠中观察到的睡眠障碍也可能由于Alfy的过度表达而减少。在Aim1，我们将 对Alfy表达、神经病理转归和睡眠行为进行相关分析，以检验 Alfy水平升高延迟睡眠相关脑内聚集突变体Htt出现的假说 这反过来又会延缓睡眠障碍的发生。在目标2中，我们将应用慢性睡眠剥夺 在症状前HD小鼠中测试睡眠障碍可能会降低蛋白质动态平衡和 通过自噬途径加速疾病进展。我们将确定睡眠不足如何影响 突变的Htt积聚和运动功能障碍。然后，我们将在HD小鼠中过度表达Alfy，并测试它是否可以 延缓SD所致的行为和神经病理改变。最后，我们将在受影响的大脑中进行rna-seq。 获得对慢性睡眠引起的转录变化的更完整描述的区域 剥夺，特别是关注维持蛋白质动态平衡的途径。