How C9orf72 RNA repeats make toxic proteins in ALS and FTD
Official title: Deciphering the structural basis of repeat-associated non-AUG (RAN) translation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia
Funded at University of Michigan at Ann Arbor · NIH-11194424 · Data updated 2026-11-12
This research looks for how a repeated RNA sequence in the C9orf72 gene creates toxic proteins that can harm people with ALS or FTD.
Quick facts
| Grant type | R01 grant |
|---|---|
| Study type | NIH-funded research |
| Funding institution | University of Michigan at Ann Arbor NIH-funded |
| Lab location | 1 site (Ann Arbor, United States) |
| Project start | September 18, 2024 |
| Project end | August 31, 2029 |
| Funding year | 2025 |
| Award (this year) | $606,736 |
| NIH project number | 5R01NS140149-02 |
| Project ID | NIH-11194424 on NIH RePORTER |
Who could benefit from this research
✓Could help
The most relevant people would be individuals with ALS or FTD who carry the C9orf72 hexanucleotide repeat expansion, or family members interested in research participation.
✕Less likely to help
People with ALS or FTD caused by other genes or without the C9orf72 repeat expansion are unlikely to see direct benefits from this project in the short term.
What this research studies
Researchers will use high-resolution cryo-electron microscopy along with lab-based biochemical and genetic tests to see how the repeated GGGGCC RNA sequence interacts with the cell’s protein-making machinery (the ribosome). They will map how translation starts without a normal start signal to produce dipeptide repeat (DPR) proteins that build up in affected brains. The team will also search for neuronal proteins that transiently bind the ribosome and promote this abnormal translation. Combining structural images with experiments should reveal the precise molecular steps that lead to toxic protein production.
Why it matters
Potential benefit: If successful, this work could reveal targets to block toxic protein production and guide new treatments for people with C9orf72-linked ALS or FTD.
How similar studies have gone: Prior studies have shown that C9orf72 repeats produce toxic DPR proteins and harm neurons, but the detailed structural mechanism of how RAN translation starts is largely untested and this cryo-EM approach is novel.
Where this research is happening
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University of Michigan at Ann Arbor
Ann Arbor, United States Active
Researchers
- Principal investigator: Brito Querido, Jailson — University of Michigan at Ann Arbor
- Study coordinator: Brito Querido, Jailson
Related research
Other NIH-funded projects on the same topics.
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Investigating how DNA damage and repair mechanisms are altered in ALS and frontotemporal dementia.
This study is looking at how problems with DNA repair might contribute to conditions like ALS and frontotemporal dementia, and it’s testing ways to fix these issues in cells from patients to help develop new treatments.
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C9orf72 ALS/FTD Prevent: prepping for future treatment
This grant aims to get ready for a preventive treatment for people who carry the C9orf72 genetic change that can lead to ALS or frontotemporal dementia.
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Understanding how a genetic repeat causes harmful protein production in ALS/FTD
Aimed at uncovering how a genetic repeat in the C9orf72 gene triggers abnormal protein production that damages nerve cells in ALS and FTD.
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Cell and tissue changes that lead to sporadic ALS and frontotemporal dementia
This project looks at how physical changes inside cells and in their tissue can make TDP‑43 protein clump in people with sporadic ALS and frontotemporal dementia.
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Investigating new treatments for frontotemporal dementia and ALS using gene editing
This study is looking at ways to help people with frontotemporal dementia and ALS by using a special gene-editing tool to fix a harmful gene that causes these diseases.
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Understanding how certain genetic repeats cause neurodegenerative diseases
This study is looking into how a specific genetic change in the C9orf72 gene causes harmful proteins to form, which are linked to ALS and Frontotemporal Dementia, and it aims to understand how this happens in nerve cells to help find better ways to tackle these conditions.
About this research
- This is an active NIH-funded research project — typically early-stage science, not a clinical trial accepting patient enrollment.
- Some NIH-funded labs run parallel clinical studies or seek volunteers for related work. To check, contact the principal investigator or institution listed above.
- For full project details, budget, and progress reports, visit the official NIH RePORTER page.