# RNA Surveillance and Protein Translation in FTD

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $536,706

## 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. Thus, it is crucial to examine relevant types
of neurons in affected brain regions in different disorders. This project focuses on studying pathogenic FUS in
forebrain cortical neurons in FTD. FUS is primarily in the nucleus, but the protein with a disease-causing mutation
mis-localizes to the cytoplasm and form dynamic membraneless granules, which can compromise cellular
functions and impair neurons. We recently showed that FTD/ALS mutations of FUS suppressed protein
translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. Thus, we hypothesize 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 pathogenic FUS
in FTD mice 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. mRNA
turnover rates and protein translation efficiency in mouse forebrains will be measured and correlated with
neuronal dysfunction and FTD disease progression. Moreover, perturbations in NMD factors and protein
translation will be examined in FTD patient tissues. Aim 2 is to identify specific proteins and mRNAs affected by
pathogenic FUS in FTD mice. We will apply proteomic approaches to identify changes in protein translation
impacted by mutant FUS in forebrain neurons. Actively translated mRNAs will be identified and quantified in
polysomes using RNA-Seq. The -omics data will be integrated for pathway analysis to reveal which specific
pathways are impaired by mutant FUS. Functional studies of affected pathways will be carry out to determine
their mechanistic relevance in 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 will evaluate the status of FUS acetylation in FTD
mice and patient tissues using a new acetylation-specific antibody we generated. We will also test how
acetylation-null and -mimicking mutations affect FUS inclusions, NMD, protein translation and neuronal...

## Key facts

- **NIH application ID:** 10070926
- **Project number:** 1R01NS115507-01A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Haining Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $536,706
- **Award type:** 1
- **Project period:** 2020-08-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070926

## Citation

> US National Institutes of Health, RePORTER application 10070926, RNA Surveillance and Protein Translation in FTD (1R01NS115507-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10070926. Licensed CC0.

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