# Regulation of paraspeckles by STAU1 in neurodegenerative disease

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $231,000

## Abstract

Project Summary/Abstract
Nuclear paraspeckles function to regulate mRNA translation. mRNAs that are sequestered in paraspeckles are
translationally silent while those not entering paraspeckles can translocate from the nucleus where the can
effectively be translated. There is now accumulating evidence that paraspeckles are increased in number and
size in neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), and
amyotrophic lateral sclerosis (ALS). RNA-binding proteins (RBPs) have a central role in neurodegenerative
disease, but their functions in paraspeckles are not well understood, yet we confirmed a critical regulatory role
of paraspeckles mediated by the stress-related RBP STAU1. In supporting studies, we discovered that STAU1
is overabundant in multiple neurodegenerative diseases including AD, FTD, and ALS, and that by normalizing
STAU1 various molecular and motor phenotypes relevant to these diseases are improved or restored. Relevant
to paraspeckles, STAU1 competes for mRNA binding at inverted repeat Alu sequences (IRAlus) with the
paraspeckle core protein p54nrb and directs mRNA translocation to the cytoplasm, for active translation. The
long noncoding RNA (lncRNA) NEAT1 is indispensable for paraspeckle formation, involving p54nrb interaction. In
our preliminary studies we found that NEAT1 is strikingly downregulated in cells depleted of STAU1. NEAT1
also interacts with TDP-43 and is overabundant in AD, FTD, and ALS. Since both NEAT1 and STAU1 are
overabundant in multiple neurodegenerative diseases, we hypothesize that normalization of STAU1 abundance
will restore NEAT1 to normal levels, thereby restoring paraspeckle function. STAU1 will likely be a better
therapeutic target than NEAT1 itself, because mice null for Neat1 have reduced cardiac function while mice null
for Stau1 are viable and are characterized by no neurodegeneration. Our proposal is divided into two specific
aims. The first aim will determine NEAT1 levels and paraspeckle localization as well as paraspeckle sizes and
numbers in cell models that have been edited to express mutant ATXN2, that interacts with STAU1 in
cytoplasmic phase-separated liquid droplets characterized by overabundant STAU1. We also evaluate Neat1
abundance and localization in a mouse model that we developed that overexpresses STAU1. In the second aim
we characterize paraspeckles and NEAT1 in cultured human cortical neurons, with focus on TDP-43 pathology.
The successful demonstration that NEAT1 is altered in diseases characterized by STAU1 overabundance will
lead to new potential therapeutic targets for AD, FTD, ALS and other disorders with abnormal nuclear
paraspeckle function, deeper understanding on the significance of NEAT1 and STAU1 to neurodegenerative
disease, and will further support STAU1 as a therapeutic target.

## Key facts

- **NIH application ID:** 10812454
- **Project number:** 5R21NS127028-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Daniel R Scoles
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $231,000
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812454

## Citation

> US National Institutes of Health, RePORTER application 10812454, Regulation of paraspeckles by STAU1 in neurodegenerative disease (5R21NS127028-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10812454. Licensed CC0.

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