Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila

破译果蝇睡眠和神经退行性变的分子相互作用

• 批准号: 10358884
• 负责人: Nancy M Bonini
• 金额: $ 71.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358884
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Behavior Therapy; Behavioral; Behavioral Model; Brain; Brain Diseases; Coupled; Data; Defect; Degenerative Disorder; Dementia; Deterioration; Dimensions; Disease; Disease Progression; Drosophila genus; Enhancers; Foundations; Frontotemporal Dementia; Functional disorder; Genes; Genetic; Genetic Screening; Genomics; Goals; Human; Impaired cognition; Investigation; Light; Link; Longevity; Mechanics; Modality; Modeling; Modification; Molecular; Molecular Genetics; Motor; Motor Neuron Disease; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurons; Pathway interactions; Phenotype; Process; Property; Proteins; RNA Interference; Research; Risk Factors; SCA2 protein; Series; Sleep; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Sleeplessness; System; TDP-43 aggregation; Testing; Therapeutic; Time; Toxic effect; Work; combat; epitranscriptomics; fly; genetic approach; human disease; improved; insight; knock-down; modifiable risk; new therapeutic target; novel; novel therapeutics; protein TDP-43; resilience; sleep abnormalities; sleep regulation

PROJECT SUMMARY Accumulating evidence strongly supports the idea that sleep is a crucial variable in neurodegenerative disease: disease progression disrupts sleep, and disrupted sleep worsens brain degeneration. Sleep is thought to represent a powerful untapped therapeutic modality through which neurodegeneration can be modified. Yet how sleep and neurodegeneration are coupled at a mechanistic level is poorly understood. Defining cellular and molecular links between sleep and neurodegeneration has been difficult, limiting the ability to pursue sleep modification as a therapeutic avenue. We propose leveraging a neurodegeneration model in Drosophila to dissect mechanisms of disrupted sleep in detail, including with high throughput genetic screens available in simple systems, with the goal of defining molecular pathways linking sleep and brain integrity. We have found that expression of the human neurodegenerative disease protein TDP43 (linked to frontotemporal dementia, Alzheimer’s and motor neuron disease) causes a robust sleep impairment. Our initial data suggest that the Drosophila sleep phenotype results from dysfunction in glia, which are known to be critically involved in sleep regulation. Moreover, TDP43-dependent sleep disturbances can be mitigated by specific modifier genes. Here we will investigate the molecular mechanisms linking TDP43-associated brain toxicity and sleep. In Aim 1, we propose to define the glial subtype critical for the sleep effect and examine how sleep loss affects the subcellular localization and accumulation of TDP43. A genetic screen for modifiers of TDP43-induced sleep dysfunction has already defined several suppressors, including Ataxin-2, a known human disease gene that interacts with TDP43 in neurons. In Aim 2, we will examine this suppressor and others in detail to define molecular and cellular mechanisms of the interaction. Finally, our preliminary data indicate that restriction of sleep opportunity (Sleep Restriction Therapy, SRT) can reverse sleep defects in TDP43 flies. In Aim 3 we will examine SRT in TDP43 flies, and conduct a genetic screen to define the molecular pathways through which SRT improves sleep in this brain degeneration model. Taken together these aims will shed new light on the molecular and genetic links between sleep dysfunction and brain degeneration, and provide the foundation for novel therapeutic targets that leverage sleep to promote brain integrity.

项目摘要 越来越多的证据强烈支持睡眠是神经退行性疾病的一个关键变量的观点： 疾病的进展会扰乱睡眠，而睡眠的中断会导致大脑退化。睡眠被认为 代表了一种强大的未开发的治疗方式，通过它可以改变神经变性。但是他又怎 睡眠和神经退行性变在机制水平上是耦合的，这一点还知之甚少。定义蜂窝和 睡眠和神经退化之间的分子联系一直很困难，限制了追求睡眠的能力 作为一种治疗手段。我们建议利用果蝇的神经变性模型， 详细剖析睡眠中断的机制，包括高通量遗传筛查， 简单的系统，目标是定义连接睡眠和大脑完整性的分子途径。 我们已经发现，人神经退行性疾病蛋白TDP 43的表达（与人神经退行性疾病蛋白TDP 43的表达相关）与神经退行性疾病蛋白TDP 43的表达相关。 额颞叶痴呆症、阿尔茨海默氏症和运动神经元疾病）会导致严重的睡眠障碍。我们最初 数据表明，果蝇睡眠表型是由神经胶质功能障碍引起的， 参与睡眠调节。此外，依赖于TDP 43的睡眠障碍可以通过特定的治疗来缓解。 修饰基因在这里，我们将研究与TDP 43相关的脑毒性相关的分子机制， 睡吧在目标1中，我们建议定义对睡眠效应至关重要的神经胶质亚型，并研究睡眠丧失如何影响神经胶质细胞的功能。 影响TDP 43的亚细胞定位和积累。对TDP 43诱导的细胞凋亡的修饰剂的遗传筛选 睡眠功能障碍已经确定了几个抑制因子，包括共济失调蛋白-2，一种已知的人类疾病基因 与神经元中的TDP 43相互作用。在目标2中，我们将详细研究此抑制器和其他抑制器，以定义 相互作用的分子和细胞机制。最后，我们的初步数据表明， 睡眠机会（睡眠限制疗法，SRT）可以逆转TDP 43果蝇的睡眠缺陷。在目标3中， 检查TDP 43苍蝇的SRT，并进行遗传筛选，以确定SRT通过的分子途径。 改善大脑退化模型的睡眠。这些目标将为分子生物学提供新的线索。 以及睡眠功能障碍和大脑退化之间的遗传联系，并为小说提供了基础 利用睡眠促进大脑完整性的治疗目标。