# RNA Surveillance and Protein Translation in FTD

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $538,460

## Abstract

Frontotemporal dementia (FTD) is an age-related non-Alzheimer dementia characterized by progressive
neuronal loss in the frontotemporal lobes. A subset of FTD is defined by the pathology of protein inclusions
positive for Fused in Sarcoma (FUS), thus named FUS-FTD. FTD and amyotrophic lateral sclerosis (ALS) share
a wide spectrum of clinical, pathological and genetic features. Pathogenic mutations of FUS cause both ALS and
FTD, and FUS proteinopathy is also detected in sporadic diseases. FUS is primarily in the nucleus, but the
protein with a disease-causing mutation mislocalizes and accumulates in the cytoplasm. Protein aggregates
induced by FUS mutations may sequester other proteins to compromise cellular functions, resulting in impaired
neurons. We recently showed that FTD/ALS mutations of FUS suppressed protein translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. The hypothesis to be tested in this project is that the
dysregulation of protein translation and mRNA surveillance contributes to cortical neuron loss in FUS-FTD.
 Three specific aims are designed to test the hypothesis using in vitro and animal models as well as FTD
patient tissues. Aim 1 is to determine how mRNA NMD and protein translation are perturbed by pathogeneic FUS
mutations in FTD mouse models and patient tissues. We will determine whether NMD factors and translation-related proteins are sequestered in FUS inclusions in forebrain neurons in R521G FUS transgenic mice at
different ages. We will measure mRNA turnover rates and protein translation efficiency in R521G FUS mice and
correlate the perturbations to neuronal dysfunction and FTD disease progression. Moreover, we will examine
whether NMD factors and protein translation proteins are sequestered in FTD patient tissues. Aim 2 is to identify
specific proteins suppressed by pathogenic FUS in FTD mice. We will apply the puromycin labeling in FTD mice
and use the proteomic approach to identify changes in protein translation impacted by mutant FUS in forebrain
neurons. In addition, actively translated mRNAs will be identified and quantified in polysome fractions using RNA-Seq. Results from the –omics approaches will be integrated for pathway analysis to reveal whether pathogenic
FUS impairs proteins in specific pathways, providing novel insights into the FTD etiology. Aim 3 is to elucidate the
significance of RNA binding and post-translational modifications in the dysfunction of pathogenic FUS. We will
use a cohort of RNA binding-deficient mutations in an optogenetic Cry2olig-FUS-mCherry system to examine
the significance of RNA binding in FUS inclusion formation and dysfunction in cortical neurons. We recently
found FUS is acetylated at residues critical to RNA binding, we will test how acetylation-null and -mimicking
mutations affect FUS inclusions, NMD and protein translation. In addition, we will also examine whether
pathogenic FUS forms RNA-dependent and -independent inclusions that produce differen...

## Key facts

- **NIH application ID:** 10449486
- **Project number:** 7R01NS115507-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Haining Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $538,460
- **Award type:** 7
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10449486

## Citation

> US National Institutes of Health, RePORTER application 10449486, RNA Surveillance and Protein Translation in FTD (7R01NS115507-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10449486. Licensed CC0.

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