Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a spectrum of devastating neurodegenerative disorders. Recently, researchers identified how ALS/FTD protein aggregation relies on specific RNA scaffolds. The C9orf72 GGGGCC-repeat expansion produces toxic RNA and dipeptide repeat proteins. These factors drive the underlying pathology. However, the exact molecular mechanisms of this process remained unclear until now.

Mechanisms of ALS/FTD Protein Aggregation

A groundbreaking study shows that GGGGCC-repeat RNA and poly(GR) form cocondensates. These interactions occur in both laboratory settings and living cells. Importantly, the RNA forms two specific shapes: G-quadruplexes and hairpins. These structures act as templates. They accelerate the transition of poly(GR) from a liquid state to a solid aggregate. Specifically, the hairpin structure creates amorphous, solid-like condensates. Consequently, these aggregates trap proteins and reduce their mobility within the cell.

Moreover, the accumulation of these cocondensates creates severe nucleolar stress. This stress triggers cellular toxicity and leads to significant dysfunction. Fortunately, targeting both RNA structures with small molecules offers a solution. This approach reduces ALS/FTD protein aggregation and restores cellular health. Thus, focusing on the RNA scaffold expands the range of potential drug targets. Ultimately, this discovery provides hope for developing more effective therapies for patients with C9orf72 mutations.

Frequently Asked Questions

What role does RNA play in ALS/FTD protein aggregation?

The GGGGCC-repeat RNA acts as a structural scaffold that speeds up the transformation of liquid protein droplets into solid, toxic aggregates known as poly(GR).

Can clinicians target RNA to treat ALS?

Yes, targeting both G-quadruplex and hairpin structures of the repeat RNA with small molecules can reduce protein aggregation and improve cellular function in experimental models.

Disclaimer: This content is for informational and educational purposes only. It does not constitute medical advice, diagnosis, or treatment. Refer to the latest local and national guidelines for clinical practice.

References

1. Liu Y et al. Condensate protein aggregation in ALS/FTD is regulated by GGGGCC-repeat RNA scaffolds. Nat Struct Mol Biol. 2026 Mar 31. doi: 10.1038/s41594-026-01785-9. PMID: 41917466.

2. Conlon EG et al. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains. eLife. 2016;5:e17820. doi: 10.7554/eLife.17820.

3. Bush JA et al. A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(G4C2)exp in c9ALS/FTD via the nuclear RNA exosome. PNAS. 2022;119(48):e2210532119. doi: 10.1073/pnas.2210532119.