# Investigating ETF1 at the Interface of Translation Repression and Nonsense-Mediated Decay in C9-ALS/FTD Neurotoxicity

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2021 · $26,659

## Abstract

PROJECT SUMMARY
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are devastating neurodegenerative
diseases that represent two ends of a single disease spectrum. A GGGGCC hexanucleotide repeat expansion in the
first intron of the C9orf72 (C9) gene is the most common genetic cause of ALS/FTD, wherein RNA and dipeptide
repeat proteins that are transcribed and translated from the C9 expansion respectively, drive neurotoxicity through a
number of toxic gain-of-function mechanisms. While several lines of evidence suggest that C9 motor neurons (MNs)
exhibit defects in nucleocytoplasmic transport, mRNA metabolism and protein translation that are tightly associated
with neurotoxicity, how these defects contribute to neurotoxicity remains unclear. In a previous proteome-wide
nucleocytoplasmic localization screen, I discovered that several proteins are redistributed in C9-expressing cells,
enriched for function in protein translation and RNA metabolism. Among these, is eukaryotic termination factor I
(ETF1), which translocates from the cytoplasm to the nucleus in C9 iPSC patient-derived MNs and C9-ALS
postmortem tissue. ETF1 associates with the scanning ribosome and mediates the balance of protein translation and
RNA degradation. Specifically, it either initiates translation termination to release a nascent polypeptide or initiates
nonsense-mediated decay (NMD) to degrade the transcript, depending on mRNA context. I hypothesize that the
change in subcellular distribution of ETF1 that I found in C9 models elicits an imbalance between protein translation
and RNA degradation through NMD, and likely represents a critical step in C9-ALS/FTD cellular pathobiology.
To test my hypothesis, the proposed experiments address two specific aims. In the first aim, I will interrogate how
ETF1 becomes redistributed and relates to C9 neurotoxicity in iPSC patient derived and isogenic control MNs. I will
determine whether ETF1 associates with three C9-related pathologies: sequestration by C9-RNA in nuclear foci,
sequestration by toxic C9 dipeptide protein products, and/or deposition within nuclear membrane invaginations. Next,
I will test the role of ETF1 in C9 disease pathogenesis by manipulating ETF1 expression in patient MNs and
measuring neuronal viability, C9-related pathology and neuronal function. In my second aim, I will examine upstream
and downstream cellular mechanisms related to the balance of protein translation and mRNA degradation through
NMD in iPSC patient derived and isogenic control MNs. I will test the role of ETF1 in mediating the balance between
protein translation and mRNA degradation by manipulating ETF1 expression in patient MNs and measuring the
efficiency of each pathway. Next, I will test for ETF1-dependent transcriptomic events that may precede neurotoxicity
by performing RNA-Seq analysis on MNs with and without NMD ablation. I will examine differentially expressed
transcripts between control and patient MNs and differential ...

## Key facts

- **NIH application ID:** 10126730
- **Project number:** 5F31NS117084-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Elizabeth Daley
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,659
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126730

## Citation

> US National Institutes of Health, RePORTER application 10126730, Investigating ETF1 at the Interface of Translation Repression and Nonsense-Mediated Decay in C9-ALS/FTD Neurotoxicity (5F31NS117084-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10126730. Licensed CC0.

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