# Oligonucleotide approach to antagonize neurotoxic TDP-43 assemblies in dementia

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $188,892

## Abstract

Cytoplasmic inclusions of the TAR DNA-binding protein of 43 kDa (TDP-43) is frequently found in
degenerating neurons of patients with Amyotrophic lateral sclerosis, Frontotemporal Dementia,
and Alzheimer’s Disease. TDP-43 is a ubiquitously-expressed, tightly-regulated, and
predominantly nuclear DNA/RNA-binding protein and the cause and mechanism underlying the
formation of TDP-43 protein inclusions remains unclear. Furthermore, modeling these inclusions
has proven challenging and it is unclear if these are neurotoxic or neuroprotective. To address
these issues, we developed an optogenetic approach to induce TDP-43 inclusions in live cells.
We show that these inclusions mimic the properties of TDP-43 inclusions found in patient neurons
that are neurotoxic. We further show that RNA binding status dictates the propensity for TDP-43
for form inclusions in live cells. In this grant, we propose to identify the characteristics of neurotoxic
TDP-43 assemblies employing our light-induced system. Specifically, we will describe the post-
translational modifications, localization, and material state of neurotoxic TDP-43 assemblies.
Since our preliminary data indicates that RNA binding state determines whether TDP-43 proteins
can oligomerize into a pathogenic conformation, we propose to study whether bait
oligonucleotides designed to bind RNA deficient TDP-43 proteins confer neuroprotection in
cortical neuron cultures, and in vivo using a TDP-43 Drosophila model system developed in our
labs. These studies have the potential to address pervasive questions regarding the neurotoxic
state of TDP-43 assemblies and the development of a new use for oligonucleotide therapeutics.

## Key facts

- **NIH application ID:** 9988341
- **Project number:** 5R21AG064940-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christopher James Donnelly
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $188,892
- **Award type:** 5
- **Project period:** 2019-08-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988341

## Citation

> US National Institutes of Health, RePORTER application 9988341, Oligonucleotide approach to antagonize neurotoxic TDP-43 assemblies in dementia (5R21AG064940-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988341. Licensed CC0.

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