# Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $643,393

## 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 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.

## Key facts

- **NIH application ID:** 10370176
- **Project number:** 1R01AG071777-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nancy M Bonini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $643,393
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370176

## Citation

> US National Institutes of Health, RePORTER application 10370176, Deciphering the molecular interplay of sleep and neurodegeneration with Drosophila (1R01AG071777-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10370176. Licensed CC0.

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