Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila

项目总结 越来越多的证据有力地支持了睡眠是神经退行性疾病的关键变量的观点： 疾病进展会扰乱睡眠，睡眠中断会加剧大脑退化。睡眠被认为是 代表了一种强大的未开发的治疗方式，通过这种方式可以改变神经退行性变。然而，如何 睡眠和神经退行性变在机械性层面上耦合在一起，人们对此知之甚少。定义蜂窝和 睡眠和神经退行性变之间的分子联系一直很困难，限制了人们追求睡眠的能力 将改良作为一种治疗途径。我们建议利用果蝇的神经退化模型来 详细分析睡眠中断的机制，包括在 简单的系统，目标是定义连接睡眠和大脑完整性的分子通路。 我们发现人类神经退行性疾病蛋白TDP43的表达(与 额颞叶痴呆、阿尔茨海默氏症和运动神经元病)会导致严重的睡眠障碍。我们最初的 数据表明，果蝇的睡眠表型是由神经胶质细胞功能障碍引起的，这是众所周知的关键 参与睡眠调节。此外，依赖TDP43的睡眠障碍可以通过特定的 修饰基因。在这里，我们将研究TDP43相关脑毒性和TDP43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，并研究睡眠损失 影响TDP43的亚细胞定位和积聚。TDP43诱导修饰物的遗传筛选 睡眠障碍已经定义了几个抑制因子，包括已知的人类疾病基因Aaxin-2 它与神经元中的TDP43相互作用。在目标2中，我们将详细研究这个抑制者和其他抑制者，以确定 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TDP43果蝇的睡眠缺陷。在《目标3》中，我们将 检查TDP43果蝇的SRT，并进行遗传筛查，以确定SRT通过的分子途径 改善这种大脑退化模型的睡眠。综上所述，这些目标将为分子研究带来新的曙光 以及睡眠障碍和大脑退化之间的遗传联系，并为新的 利用睡眠促进大脑完整性的治疗目标。

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.