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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：
10370176
负责人：
Nancy M Bonini
金额：
$ 64.34万
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/10370176
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 Investigation Light Link Longevity Mechanics Modality Modeling Modification Molecular Molecular Genetics Motor Neuron Disease 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 genetic approach human disease improved 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.

项目总结