# Investigating the role of Serine Arginine (SR)-Rich RNA Binding Proteins in Tau Aggregation

> **NIH NIH F31** · EMORY UNIVERSITY · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by extracellular β-amyloid (Aβ),
microtubule-associated protein tau intracellular neurofibrillary tangles (NFTs), cellular loss, and cognitive decline.
NFTs correlate significantly to the onset of clinical symptoms, yet current disease-modifying therapies do not
target tau aggregation mechanisms. Pathogenic misfolded tau propagates across neuronal cells in AD and
causes a ‘gain-of-function’ misfolding of normal tau proteins in a templated manner. Evidence from our group
and others has identified specific RNA-binding proteins (RBPs) that co-aggregate with pathological tau in AD
brains. A majority of these RBPs are insoluble, mislocalized to the cytoplasm, and display loss of splicing function
in AD. Importantly, a specific class of RBPs that correlate with increased AD pathology and cognitive decline in
AD contain disordered low complexity (LC) structural domains that are rich with serine and arginine residues
(SR-rich). It is currently unknown if SR-rich RBPs alter tau aggregation in disease. I propose that this class of
RBPs has distinct interactions with tau in AD through their SR-rich LC domains. My central hypothesis is that
RBPs co-aggregating with tau in AD will seed and enhance tau aggregation via the SR-rich LC domain. I will use
a combination of biochemical, cellular, and in vitro assays to examine how SR-rich LC domains alter tau
aggregation. The long-term goal of this project is to identify points of therapeutic intervention by modulating tau
aggregation in AD and enhancing our mechanistic understanding of the aggregation process. Aim 1 will
determine if RBPs mediate tau aggregation via SR-rich LC domains through co-localization with tau fluorescent
reporter cells and thioflavin-T fibrillization experiments. In Aim 2, I will identify co-aggregating RBPs through a
novel tau proximity labeling system in mammalian cells. This proteomic screen provides the ability to resolve
additional co-aggregating RBPs through mass spectrometry techniques and subsequent bioinformatic analyses.
These two parallel aims will allow me to determine mechanisms that underlie tau seeding and aggregation in
disease. By understanding how the SR-rich LC domain of RBPs implicated in AD promote tau aggregation, I will
contribute to the understanding of AD pathological proteins and provide impactful insight toward therapeutic
targets to reduce tau burden. The training provided through successful completion of the proposal aims will
significantly prepare me for a career as an independent researcher in neurodegeneration.

## Key facts

- **NIH application ID:** 10899529
- **Project number:** 5F31AG079670-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Sarah Shapley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899529

## Citation

> US National Institutes of Health, RePORTER application 10899529, Investigating the role of Serine Arginine (SR)-Rich RNA Binding Proteins in Tau Aggregation (5F31AG079670-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10899529. Licensed CC0.

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