# Determine the neurotoxicity of RNA metabolism dysfunction caused by cytoplasmic TDP-43 aggregates

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $616,468

## Abstract

This proposal seeks to determine how TDP-43 protein aggregates dysregulate P-body function in
neurons and subsequently produce neurotoxicity. Cytoplasmic aggregation of TDP-43 has been reported in
nearly every age-dependent neurodegenerative disease, including in >40% of frontotemporal dementia (FTD),
in the hippocampal neurons of Alzheimer’s disease (AD) patients, in >90% of ALS. It also defines a recently
recognized AD-like dementia in the oldest elderly, an AD-like syndrome named Limbic-predominant Age-
related TDP-43 Encephalopathy (LATE). We have identified that TDP-43 cytoplasmic aggregates regulate the
liquid-liquid phase separation (LLPS) of RNA processing bodies (P-bodies) in neuron-like cells and
postmortem spinal cord motor neurons in ALS patients. P-bodies are cytoplasmic membraneless
ribonucleoprotein (RNP) granules composed of RNAs and protein complexes involved in translational repression
and mRNA decay. Neurons carry a high number of P-bodies in the soma. We hypothesize that TDP-43
aggregation causes neuronal toxicity by disrupting the morphology and function of P-bodies. Our
proposal is highly innovative because how TDP-43 proteinopathy regulates the LLPS of other membraneless
organelles has not been reported in vivo. We propose to use cutting-edge imaging, proteomic, and sequencing
approaches to determine the protein and RNA composition of neuronal P-bodies and how it changes in response
to TDP-43 aggregation in vivo. We will first determine how TDP-43 cytoplasmic aggregates initiate P-body
disassembly and then determine the RNA metabolism change in neurons carrying TDP-43 aggregates or
defective P-bodies. Lastly and importantly, we will determine whether P-body proteins and RNA can serve as
pathological markers for AD-related dementia, such as LATE.

## Key facts

- **NIH application ID:** 10931669
- **Project number:** 5R01NS133517-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Sarah H Shahmoradian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,468
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931669

## Citation

> US National Institutes of Health, RePORTER application 10931669, Determine the neurotoxicity of RNA metabolism dysfunction caused by cytoplasmic TDP-43 aggregates (5R01NS133517-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931669. Licensed CC0.

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