# Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA

> **NIH NIH F30** · UNIVERSITY OF COLORADO · 2022 · $39,127

## Abstract

PROJECT SUMMARY/ABSTRACT
Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA
 Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive, fatal
neurodegenerative diseases. The most common cause of hereditary ALS and FTD is an expansion of the G4C2
sequence in an intron of the C9orf72 gene (c9ALS/FTD). A hallmark pathologic feature of c9ALS/FTD is the
presence of repeat expansion RNA foci in neuronal nuclei, which is unusual because introns are usually
degraded too rapidly to be easily detected. The accumulating G4C2 repeat expansion RNA is thought to
contribute to c9ALS/FTD disease development in two ways: it can sequester RNA-binding proteins and disrupt
their function, and it can be exported into the cytoplasm for translation into toxic dipeptide repeat proteins.
The persistence of the repeat expansion RNA suggests that it forms a stable RNA structure that resists the
normal intron degradation machinery. However, eukaryotic cells contain specific mechanisms for the
degradation of RNAs with strong secondary structures. Such RNAs are post-transcriptionally modified with 3'
oligo-uridine or oligo-adenosine tails that then recruit processive 3' to 5' exonucleases to degrade the RNA. I
hypothesize that the C9orf72 repeat RNA is a poor substrate for normal intronic degradation pathways and that
3’ end tailing determines its rate of decay. To test this, the goal of this proposal is two-fold: I will determine the
composition of the repeat expansion RNA that accumulates into nuclear foci to learn where intronic
degradation is stalling (Aim 1), and I will examine the changes to the sequence and levels of the
G4C2 repeat expansion RNA in response to perturbations to 3’ end tailing, tail removal, and RNA degradation
(Aim 2). Taken together, these studies present an exciting opportunity to discover the mechanisms that
promote degradation of the toxic repeat expansion RNA and, potentially, the ability to accelerate its decay to
reduce toxicity. If successful, the knowledge gained from this work could guide future therapeutic design for
c9ALS/FTD.

## Key facts

- **NIH application ID:** 10387697
- **Project number:** 1F30AG076323-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Soraya I Shehata
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,127
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387697

## Citation

> US National Institutes of Health, RePORTER application 10387697, Understanding and Manipulating the Degradation of the C9orf72 Repeat Expansion RNA (1F30AG076323-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10387697. Licensed CC0.

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