# The Role of RNA in Tau Aggregation

> **NIH NIH F30** · UNIVERSITY OF COLORADO · 2020 · $34,092

## Abstract

PROJECT SUMMARY: Tauopathies are a group of neurodegenerative diseases characterized by aggregates of
the Microtubule Associated Protein Tau (tau) found in the brains of patients on autopsy. These disorders include
Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). AD
alone is the 6th leading cause of death in the US (affecting more than 5.7 million), no cure is currently available,
and the number of patients is expected to substantially increase in the coming years.
 Tauopathies can be caused by mutations in tau that promote its aggregation (as in FTD) or by
extracellular stressors that trigger tau aggregation (as in AD and CTE). How extracellular stressors lead to
intracellular tau aggregation is unknown. A number of recent observations indicate that stress granules
(SGs), a type of cytosolic RNA and protein assembly that forms in response to cellular stress, might be involved
in the formation and persistence of tau aggregates and manipulating SGs could indicate new therapeutic
strategies. I propose a model where cellular stressors (e.g., neuroinflammation, viral infection, amyloid-b)
promote the formation of SGs that recruit tau. SGs create high local concentrations of tau and RNA that nucleate
and stabilize tau aggregates and contribute to their toxicity. This model is supported by in vitro and in vivo
evidence suggesting that RNA promotes tau aggregation, RNA is sequestered into tau aggregates in AD patient
brains, and that reducing SG formation decreases tau toxicity.
 My preliminary data shows that stress granules induced by the neuroinflammatory compound,
prostaglandin J2, colocalize with tau. I have also shown by electron microscopy and thioflavin T fluorescence
that incubating RNA with tau in vitro causes the formation of tau aggregates made up of paired helical filaments
that contain RNA. Finally, I have shown by RNAseq and by single molecule fluorescence in situ hybridization
(smFISH) that in vivo tau aggregates contain a diversity of RNAs (rRNAs, mRNAs, snRNAs, and lncRNAs) and
some RNAs are more enriched than others.
 Aim 1 of this proposal will identify and manipulate the levels of RNAs that are bound by tau in
unaggregated and aggregated states in disease relevant model systems. Successful completion of this aim will
suggest 1) what set of RNAs act as cofactors for tau aggregation, 2) whether the RNAs in tau aggregates are similar
to SGs, and 3) whether sequestration of specific RNAs contributes to tau toxicity. Aim 2 of this proposal will
manipulate SG formation and RNA stability and then measure how these manipulations influence tau
aggregation. Results of this aim will determine what role RNA and SGs play in the formation and persistence of
tau aggregates. Broadly, this proposal aims to test the hypothesis that SGs link extracellular stress and
intracellular tau aggregation with the hope of identifying new therapeutic strategies to treat debilitating
neurodegenerative diseases s...

## Key facts

- **NIH application ID:** 9991601
- **Project number:** 5F30AG063468-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Evan T Lester
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $34,092
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991601

## Citation

> US National Institutes of Health, RePORTER application 9991601, The Role of RNA in Tau Aggregation (5F30AG063468-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991601. Licensed CC0.

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