# Investigating the loss of terminal neuronal differentiation as a novel mechanism driving neuronal death in Alzheimer's disease and related tauopathies

> **NIH NIH F31** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $27,804

## Abstract

PROJECT SUMMARY
Tauopathies are a class of neurodegenerative disorders associated with deposits of insoluble tau protein within the
brain. At over 5 million cases currently diagnosed among Americans, Alzheimer’s disease (AD) is the most common type
of tauopathy. With no therapies that significantly slow or alter the disease course for AD, the number of Americans
diagnosed with AD is expected to increase to 16 million by the year 2050. As one of two hallmark pathologies of AD,
pathogenic tau has emerged as a promising target for therapeutic targeting. Mutations in the tau gene are associated
with dominantly inherited familial tauopathies termed frontotemporal dementia with parkinsonism linked to
chromosome 17 (FTDP-17), demonstrating that tau dysfunction is sufficient to drive neurodegeneration. The goal of this
proposal is to understand the specific cellular processes that connect pathogenic tau to neurodegeneration in AD and
related tauopathies, and to target these processes pharmacologically. An active cellular program maintains the
terminally differentiated, post-mitotic state of neurons. When this program is perturbed, post-mitotic neurons can re-
activate the cell cycle, which is known to drive neuronal death. In my preliminary analyses, I have identified prospero
and staufen, two proteins that orchestrate the expression and silencing of genes that maintain terminal neuronal
differentiation, among the top ten significantly downregulated genes in brains of a Drosophila model of tauopathy. In
addition, I also identified 51 genes that are differentially expressed in tau transgenic Drosophila that are known to be
regulated by prospero and staufen, suggest that pathogenic tau may disrupt the cellular program that maintains
terminal neuronal differentiation. In addition, previously identified cellular phenotypes in tauopathy share many
overlapping phenotypes with dedifferentiated cancerous cells and neural stem cells, including presence of nuclear
envelope invaginations, heterochromatin decondensation, expression of development-associated genes, and cell cycle
activation. In this proposal, I will test the hypothesis that pathogenic tau leads to neuronal death by dysregulating
prospero and staufen, thereby disrupting the cellular program that maintains terminal neuronal differentiation in
neurons. In Aim I, I will determine the mechanistic cause and downstream consequences of prospero depletion. In Aim
2, I will determine if loss of terminal neuronal differentiation mediates neuronal death in tau transgenic Drosophila. In
Aim 3, I will determine whether maintaining neuronal differentiation is a viable therapeutic strategy for preventing
neuronal death in tauopathy. My findings will identify new targets for therapeutic development for AD and related
tauopathies, as well as other disorders involving loss of terminal differentiation.

## Key facts

- **NIH application ID:** 10006595
- **Project number:** 5F31NS108657-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Paul Adrian Beckmann
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $27,804
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006595

## Citation

> US National Institutes of Health, RePORTER application 10006595, Investigating the loss of terminal neuronal differentiation as a novel mechanism driving neuronal death in Alzheimer's disease and related tauopathies (5F31NS108657-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10006595. Licensed CC0.

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