Deciphering the molecular interplay of sleep and neurodegeneration with drosophila

This Project Grant from the National Institute on Aging, part of the Department of Health and Human Services, will fund research into the molecular interplay of sleep and neurodegeneration using the Drosophila model system. With $2.14 million provided over 11 months, the Trustees of the University of Pennsylvania will investigate how expression of the TDP-43 protein linked to neurodegenerative diseases disrupts sleep in fruit flies. Researchers will aim to define the specific glial subtypes and molecular pathways involved, including conducting genetic screens. They will also examine how restricting sleep opportunity can potentially reverse sleep defects in the TDP-43 flies. Findings seek to shed light on the biological links between sleep dysfunction and brain degeneration, with the goal of informing novel therapeutic targets leveraging sleep to promote neural integrity. The award advances the objectives of the Aging Research program under the CFDA to support biomedical research on understanding aging and age-related diseases.

Abstract

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.