# Effects of frontotemporal dementia-associated Tau mutations on nuclear organization in a Drosophila melanogaster human tauopathy model

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY:
Frontotemporal dementia (FTD) is a neurodegenerative disease associated with mutations in the microtubule
binding protein Tau. Average age of FTD onset is 49 years old with a life expectancy of 8.5 years. The clinical
presentation of FTD is heterogeneous with patients exhibiting parkinsonism, dementia, atrophy in the temporal
lobes, and personality changes. Current treatments can mitigate aspects of the behavioral changes associated
with FTD, however, no therapies are available to slow the progression. Since patient sample procurement is
restricted to post-mortem tissue, our understanding of the progression and underlying pathogenic mechanisms
of this disease is limited, and to address these issues requires the use of model organisms. Recent work in
model systems and post-mortem tissue has shown that expression of FTD-associated mutant Tau may lead to
epigenetic modifications that alter gene expression. In our lab, we model FTD using Drosophila, which allowed
us to conduct longitudinal studies to observe FTD progression throughout the adult lifespan. This revealed that
adult Drosophila expressing FTD-associated mutant human Tau (hTau) have age-dependent neurodegenerative
vacuoles, axonal changes, locomotion defects and impaired memory while flies expressing normal hTau did not.
This confirms that our models show pathogenic phenotypes associated with Tauopathies and it provides the
basis to now use these models to identify molecular mechanisms of pathogenicity. In this proposal, I hypothesize
that FTD mutant Tau alters heterochromatin distribution, which disrupts gene expression and chromatin structure
producing or contributing to the behavioral and neurodegenerative phenotypes seen in FTD pathology. In
addition, I hypothesize that the gene regulatory networks will vary depending on the FTD mutation as each
mutation is clinically distinct. I propose to test this hypothesis with the following aims: (1) Use single-cell omics
to assess how human Tau FTD mutations alter chromatin accessibility and gene expression in the young and
aged adult Drosophila brain, (2) Probe nuclear architecture changes by mapping heterochromatin regions in the
hTauK369I FTD Drosophila model, (3) Determine the role of novel candidate genes in our FTD Drosophila model
through genetic interaction tests. Utilizing single-cell technology will allow us to understand how the mutant Tau
affects distinct cell types in the brain and it may identify cell-type-specific candidates, and lead to the
development of targeted therapies.

## Key facts

- **NIH application ID:** 10783770
- **Project number:** 5F31AG076251-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Eve Lowenstein
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2022-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783770

## Citation

> US National Institutes of Health, RePORTER application 10783770, Effects of frontotemporal dementia-associated Tau mutations on nuclear organization in a Drosophila melanogaster human tauopathy model (5F31AG076251-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10783770. Licensed CC0.

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