# Molecular mechanism of dipeptide repeat protein production from hexanucleotide repeats in C9ORF72-related ALS and FTD

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $358,203

## Abstract

PROJECT SUMMARY
Hexanucleotide repeat expansion in a non-coding region of C9orf72 is the most common genetic cause of both
amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD). One potential pathogenic mechanism
is the aberrant accumulation of dipeptide repeat (DPR) proteins produced by repeat-associated non-AUG
(RAN) translation in all six reading frames (poly-GA, poly-GR, poly-PA, poly-PR and poly-PG) of both sense
and antisense RNAs. Abnormal cytoplasmic inclusions of these DPR proteins have been found in C9ORF72
patient tissues and cells. Several lines of evidence indicate that some forms of the DPR proteins can be
pathogenic, yet little is known how the DPRs are generated from the expanded repeats. The goal of this
proposal is to understand the molecular mechanisms and identify genetic modifiers of DPR production from
both sense and antisense repeats, combining the genome-scale CRISPR/Cas9 knockout screening technology
with biochemical and molecular approaches. We will primarily focus on two major steps of repeat RNA
processing that could influence the final protein expression level: RNA nuclear export and RAN translation. We
will dissect the molecular pathways of nuclear export for both sense and antisense repeats, what factors
mediate this process, and how this is affected by C9-mediated toxicity on nucleocytoplasmic transport. We will
decipher the molecular mechanisms of C9 RAN translation, and examine whether there are common modifiers
between sense and antisense repeats. Altogether, these studies can provide novel insights on how DPRs are
produced from C9 repeats and what approaches can be taken to prevent it. This will guide the development of
research tools to understand how DRPs contribute to the disease pathogenesis. It will also possibly provide
potential therapeutic targets to reduce DPR-mediated toxicity by inhibiting their production.

## Key facts

- **NIH application ID:** 10378768
- **Project number:** 5R01NS107347-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Shuying Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $358,203
- **Award type:** 5
- **Project period:** 2018-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378768

## Citation

> US National Institutes of Health, RePORTER application 10378768, Molecular mechanism of dipeptide repeat protein production from hexanucleotide repeats in C9ORF72-related ALS and FTD (5R01NS107347-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10378768. Licensed CC0.

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