# Hexanucleotide repeat translation in ALS and Frontotemporal Dementia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $454,462

## Abstract

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD) are common neurodegenerative
disorders that are progressive, fatal, and without effective treatment. Recently, the most common known
cause of ALS and FTD was identified as an intronic GGGGCC hexanucleotide repeat expansion in the gene
C9orf72 (C9FTD/ALS). This repeat triggers synthesis of toxic proteins via a process known as Repeat
Associated Non-AUG (RAN) Translation. These RAN peptides kill neurons and are sufficient to cause
neurodegeneration in model systems. We know very little about how RAN translation at C9 repeats (C9
RANT) actually occurs. The objective of this proposal is to determine the mechanisms underlying C9 RAN and
to identify methods of blocking it as a first step towards novel therapeutic development. Our central hypothesis
is that C9 RAN utilizes a non-canonical translational initiation pathway that can be selectively blocked.
Moreover, we predict that preventing C9 RAN will stop neurodegeneration elicited by GGGGCC repeats. To
test these hypotheses, we developed robust and quantitative in vitro and cell based assays of C9 RANT, as
well as a collection of models derived from patient induced pluripotent stem cells, rodent neurons, and
Drosophila. Using these tools, we will define the mRNA species that undergo C9 RANT, identify the critical
RNA and protein based factors that allow for C9 RANT and test whether suppressing C9 RANT by modulating
the surrounding sequence or protein factors can block toxicity in model systems. Together, these studies
should provide us with a working map of how C9 RAN occurs and what steps can be taken to prevent it. This
project has broad reaching implications both for our understanding of how RAN translation contributes to
disease as well as providing a logical path towards therapeutic development in C9FTD/ALS and other
neurodegenerative nucleotide repeat disorders.

## Key facts

- **NIH application ID:** 9920791
- **Project number:** 5R01NS099280-05
- **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:** 2020
- **Award amount:** $454,462
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920791

## Citation

> US National Institutes of Health, RePORTER application 9920791, Hexanucleotide repeat translation in ALS and Frontotemporal Dementia (5R01NS099280-05). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/9920791. Licensed CC0.

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