# Hexanucleotide repeat translation in ALS and Frontotemporal Dementia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $670,796

## Abstract

Hexanucleotide repeat translation in ALS and Frontotemporal Dementia
The most common genetic cause of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia
(FTD) is an intronic GGGGCC (G4C2) hexanucleotide repeat expansion in the gene C9orf72
(C9FTD/ALS). Despite its position within an intron, the C9orf72 repeat triggers synthesis of dipeptide
repeat proteins (DPRs) via a process known as Repeat Associated Non-AUG (RAN) Translation. Studies
by our group and others over the past decade have defined key mechanistic parameters that regulate
RAN translational initiation and identified selective modulators of RAN translation that suppress disease
relevant phenotypes in model systems.
In this renewal application, we will address two key questions. 1) What mRNA template(s) are used for
C9RAN translation endogenously? Some data suggests that repeat-containing lariats are stabilized and
translated. We propose an alternative model where aberrant transcription initiation within the intron itself
generates linear 5’ M7G capped mRNA species that robustly support RAN translation. 2) What impact
does repeat RNA structure have on C9RAN translational initiation and elongation? Our preliminary
studies suggest that both repeat RNA structure dynamics and ribosomal quality control (RQC) pathways
act as critical modulators of RAN translation by eliciting ribosomal stalling and altering translational
initiation and elongation rates.
Our central hypothesis is that GC-rich repeats generate aberrant mRNA species whose RNA structure
directly influences their capacity for translation and neurotoxicity. Our goals are to determine the relative
contributions of different potential endogenous mRNA species to C9RAN translation and the impact of
repeat RNA structure on RAN translational efficiency and RQC engagement. Our central premise is that
a detailed understanding of C9RAN translation will both uncover potential therapeutic targets for repeat
expansion disorders including C9 FTD/ALS and reveal novel biological insights into aberrant translation
events in neurons. In sum, this work will rigorously explore the mechanisms underlying C9 RAN
translation, enhance our understanding of protein translational dynamics in neurons and repeat
expansion disorder pathogenesis while simultaneously providing a rational path towards therapeutic
development in ALS and FTD.

## Key facts

- **NIH application ID:** 10818543
- **Project number:** 5R01NS099280-07
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Peter K Todd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $670,796
- **Award type:** 5
- **Project period:** 2016-09-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818543

## Citation

> US National Institutes of Health, RePORTER application 10818543, Hexanucleotide repeat translation in ALS and Frontotemporal Dementia (5R01NS099280-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10818543. Licensed CC0.

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