# Deciphering the structural basis of repeat-associated non-AUG (RAN) translation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $681,536

## Abstract

Expansion of a hexanucleotide GGGGCC repeat within the first intron of the C9orf72 gene is the
primary monogenic cause for both Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal
Dementia (FTD). Despite its intronic location, expanded GGGGCC repeat is retained in the
mature mRNA, supporting a non-canonical translation initiation mechanism known as repeat-
associated non-AUG (RAN) translation. RAN translation of C9orf72 mRNA generates toxic
dipeptide repeat (DPR) proteins. These DPR proteins aggregate in the brains of affected
individuals and have been shown to induce neurodegeneration in model systems. Despite the
medical and biological importance of RAN translation, a fundamental question remains
unanswered: how does RAN translation initiate? To address this question, this proposal will use
cryo-electron microscopy along with biochemical and genetic approaches to determine how
expanded GGGGCC repeats physically interact with the ribosome to induce this spurious start
site selection in ways that generate DPR proteins. Simultaneously, we will determine the role of
protein factors that may bind to the translation initiation complex in neurons and promote RAN
translation of C9orf72 mRNA.
The innovative approach outlined in this proposal will allow us to address some fundamental
questions about mRNA translation initiation in the native environment, specifically identifying
protein factors that bind transiently to the ribosomal complex with low affinity and their role in the
regulation of RAN translation. Moreover, this proposal will provide a novel tool for studying various
neurodegenerative diseases and neuronal functions associated with aberrant mRNA translation.
Taken together, our work will provide insights into the molecular mechanism underlying RAN
translation initiation while providing insights into the contribution of this aberrant translation to ALS
and FTD.

## Key facts

- **NIH application ID:** 11024129
- **Project number:** 1R01NS140149-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jailson Brito Querido
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $681,536
- **Award type:** 1
- **Project period:** 2024-09-18 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11024129

## Citation

> US National Institutes of Health, RePORTER application 11024129, Deciphering the structural basis of repeat-associated non-AUG (RAN) translation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (1R01NS140149-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11024129. Licensed CC0.

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