# Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila

> **NIH NIH R56** · UNIVERSITY OF PENNSYLVANIA · 2021 · $712,984

## Abstract

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.

## Key facts

- **NIH application ID:** 10358884
- **Project number:** 1R56AG071777-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nancy M Bonini
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $712,984
- **Award type:** 1
- **Project period:** 2021-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358884

## Citation

> US National Institutes of Health, RePORTER application 10358884, Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila (1R56AG071777-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10358884. Licensed CC0.

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