# Supplement -- The pathogenic relationship between neuronal activity and C9orf72-linked  neurodegeneration

> **NIH NIH RF1** · THOMAS JEFFERSON UNIVERSITY · 2021 · $390,000

## Abstract

ABSTRACT
The nucleotide repeat expansion (NRE) mutation located in the chromosome 9 open reading frame 72
(C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral
sclerosis (ALS), which exist in a spectrum of neurological and neuromuscular disorders. The C9orf72-NRE
mutation leads to several cellular abnormalities, including the accumulation of toxic dipeptide repeats (DPRs),
which often appear in clinically affected tissues that degenerate in FTD/ALS. Sleep disorders are common in
Alzheimer’s disease (AD) and AD related dementia (ADRD) patients, and accumulating evidence suggests
that the relationship between sleep/circadian disruptions and AD/ADRD is bi-directional. While AD/ADRD
causes sleep disturbances/circadian disruption, disrupted sleep/circadian rhythms can accelerate AD/ADRD
pathologies, and reduced sleep is associated with an increased risk of late-onset dementia. Moreover, animal
studies suggest that sleep interventions could reverse cognitive deficits in AD models. Although sleep and
circadian disorders are frequently associated with FTD/ALS and have been reported for patients carrying the
C9orf72-NRE mutation, it is unknown if sleep manipulations can modify disease progression. Building on our
recent in vitro findings linking aberrant neuronal activity to increased dipeptide repeat (DPR) toxicity, the
parent award aims to test whether aberrant neuronal activity modifies C9orf72-NRE-linked neurodegeneration
using novel patient derived neuronal models and then validate these findings using mouse models. In this
supplemental project, we propose to examine the relationship between sleep and FTD pathologies in both
Drosophila and mouse models of the C9orf72 NRE mutation. In Aim 1, we will examine the sleep and short-
term memory (STM) phenotypes of the Drosophila models and test whether sleep and excitability
manipulations can modify C9orf72 NRE behavioral phenotypes and cellular abnormalities. In Aim 2, we will
determine the effects of sleep deprivation on FTD-relevant behavioral defects and cellular pathologies in
mouse models. We expect that the innovative and synergistic animal model research will establish a critical
foundation for advancing our understanding of the bidirectional relationship between sleep and C9-NRE-inked
dementia.

## Key facts

- **NIH application ID:** 10401973
- **Project number:** 3RF1NS114128-01A1S1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Aaron Raymond Haeusler
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 3
- **Project period:** 2021-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401973

## Citation

> US National Institutes of Health, RePORTER application 10401973, Supplement -- The pathogenic relationship between neuronal activity and C9orf72-linked  neurodegeneration (3RF1NS114128-01A1S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10401973. Licensed CC0.

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