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

基本信息

批准号：
10554337
负责人：
Nancy M Bonini
金额：
$ 62.88万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554337
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos 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 Intervention Investigation Link Longevity Mechanics Modality Modeling Modification Molecular Motor Neuron Disease Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Pathology 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 abeta accumulation combat epitranscriptomics fly gene interaction genetic approach human disease improvement on sleep insight knock-down modifiable risk new therapeutic target novel novel therapeutics protein TDP-43 resilience sleep abnormalities sleep regulation

项目摘要

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 use of 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 Alzheimer’s, frontotemporal dementia, 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. Importantly, expression of TDP43 in glia also causes brain degeneration and shortened lifespan in flies, providing a strong rationale for investigation of TDP43 as a key link between sleep and neurodegeneration. Because TDP43 pathology has been described in many human neurodegenerative diseases including Alzheimer’s, focused study of the mechanisms linking TDP43 with sleep are likely to be broadly relevant. Here we will investigate the molecular mechanisms linking TDP43-associated brain degeneration 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 preliminary 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.

项目摘要积累的证据强烈支持这样的观念，即睡眠是神经退行性疾病的关键变量：疾病进展会破坏睡眠，而睡眠干扰会使脑退化恶化。有人认为睡眠表示可以修改神经变性的强大未开发的治疗方式。但是怎么样睡眠和神经变性在机械水平上耦合得很糟糕。定义细胞和睡眠和神经退行性之间的分子联系很困难，限制了追求睡眠的能力修改为治疗大道。我们建议在果蝇中利用神经退行性模型详细解剖睡眠中断的机制，包括使用高吞吐量遗传筛选简单系统，目的是定义将睡眠和大脑完整性联系起来的分子途径。我们发现人神经退行性疾病蛋白TDP43的表达（链接到阿尔茨海默氏症，额颞痴呆和运动神经元疾病）会造成强大的睡眠障碍。我们的最初数据表明，果蝇睡眠表型是由于神经胶质中的功能障碍引起的，已知这是至关重要的参与睡眠调节。重要的是，TDP43在Glia中的表达也会引起脑变性和苍蝇缩短了寿命，为TDP43的投资提供了强烈的理由，作为睡眠之间的关键联系和神经变性。因为TDP43病理已在许多人类神经退行性中描述包括阿尔茨海默氏症的疾病，重点研究将TDP43与睡眠联系起来的机制可能是广泛相关。在这里，我们将研究与TDP43相关脑变性和睡觉。在AIM 1中，我们建议定义对睡眠效应至关重要的神经胶质亚型影响TDP43的亚细胞定位和积累。修饰符的初步遗传筛选 TDP43诱导的睡眠功能障碍已经定义了几种补充剂，包括Ataxin-2，已知的人与神经元中TDP43相互作用的疾病基因。在AIM 2中，我们将详细检查该抑制器和其他抑制器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的限制（睡眠限制疗法，SRT）可以逆转TDP43苍蝇的睡眠缺陷。在 AIM 3我们将检查TDP43蝇中的SRT，并进行遗传筛选以定义分子途径在此大脑变性模型中，SRT改善了睡眠。总之，这些目标将使新的睡眠功能障碍与脑退化之间的分子和遗传联系的光明，并提供利用睡眠来促进大脑完整性的新型治疗靶基础。