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/文摘