A team of researchers from the Department of Molecular Biology & Genetics at Aarhus University, has developed a new strategy to eliminate disease-causing proteins in human cells. Using artificially engineered circular RNA molecules (circRNAs), they successfully targeted and degraded toxic RNA-binding proteins that play a central role in the development of amyotrophic lateral sclerosis (ALS).

ALS, also known as Lou Gehrig's disease, affects nerve cells that control muscle movement, leading to progressive paralysis and typically a life expectancy of just 2-5 years after diagnosis. The disease often involves faulty versions of proteins that normally help cells process RNA but instead accumulate as so-called “condensates” within cells, becoming toxic.

The study has just been published in the international journal Molecular Therapy - Methods & Clinical Development.

A new molecular cleanup crew

The research team designed circular RNA molecules that act like molecular scaffolds, bringing together two key players: the problematic ALS-associated proteins and a cellular "cleanup enzyme" called RC3H2. This enzyme naturally tags unwanted proteins for destruction by the cell's waste disposal system.

"Think of it like introducing a matchmaker that brings together a problem protein with the cell's recycling system," Anne Kruse Hollensen explains.

In laboratory tests, the researchers successfully used engineered circular RNAs to reduce levels of two key ALS-associated proteins, called FUS and hnRNPA1 that harbour specific mutations.

A step toward new treatments

This is the first time circRNAs have been used in this way to trigger degradation of disease-associated proteins. The approach, though still at a preliminary stage, offers promising avenues for treating ALS and potentially other neurodegenerative diseases.

"Our results show that it’s possible to design RNA molecules that control the degradation of specific proteins. That gives hope for new therapeutic strategies in neurodegenerative diseases," says Christian Kroun Damgaard.

"There is still a long road ahead before this might eventually be used in the clinic," he adds, "but our findings are an important proof-of-concept that circRNAs can be used to regulate protein function inside cells".

This research was published in Molecular Therapy Methods & Clinical Development by Anne Kruse Hollensen, Matilde Helbo Sørensen, Sofie Vesterbæk Thomsen, Henriette Sylvain Thomsen, and Christian Kroun Damgaard from the Department of Molecular Biology and Genetics at Aarhus University. Link to publication: https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(25)00120-2

For further information:

Christian Kroun Damgaard, ckd@mbg.au.dk, +45 29888670

Anne Kruse Hollensen, annek@mbg.au.dk, +45 21674790.