ALS-Linked Protein FUS Plays Major Role in Gene Expression, Study Finds

Scientists have discovered a key role for the ALS-linked protein known as fused in sarcoma (FUS) in a system that is crucial to regulating gene expression.

The study, “FUS Regulates Activity of MicroRNA-Mediated Gene Silencing,” was published in the journal Molecular Cell.

FUS is a DNA/RNA-binding protein involved in repairing damaged DNA inside the nucleus. RNA-binding proteins play important roles in regulating gene expression. Mutations in the FUS gene have also been linked to ALS cases. But the protein’s exact role in gene expression and how it relates to ALS are still not clear.

Researchers at the Johns Hopkins Bloomberg School of Public Health set out to clarify how important FUS is to this process.

They found that FUS is a key player in a system called the miRNA-induced silencing complex (miRISC), which regulates protein production.

This complex consists of microRNAs (miRNAs), small RNAs that help regulate the translation of genes into proteins, that are loaded onto one of four Argonaute (AGO) proteins. MiRNAs guide the complex to specific protein-coding RNA targets, silencing the gene and stopping protein production. The mechanism plays an important part in keeping cells healthy and functioning.

Researchers first discovered that FUS binds to a protein called Argonaute2 (AGO2), a part of the AGO family. Next, they showed that in cells that lacked FUS, there was a substantial decrease in miRNA silencing activity.

This result was also seen in cells that carried a mutant, ALS-linked version of FUS. The mutant FUS led to decreased binding of FUS to AGO2, indicating that FUS likely affects miRNA-mediated gene silencing through its interaction with AGO2.

It was also found that a substantial portion of the gene types affected by the mutant FUS played roles in neural development and disease, implicating the protein as a potential regulator of gene expression in brain processes.

Next, researchers showed that a distant version of FUS, which exists in a worm called C. elegans, was required for maximizing the efficiency of microRNA-mediated gene silencing. C. elegans is regularly used in laboratory settings to study human diseases. These results suggest that FUS plays a similar role in mammals as well.

“It is thought to be a challenge for Argonaute proteins and microRNAs to find messenger-RNA targets efficiently,” Jiou Wang, MD, PhD, lead author of the paper and an associate professor in the Bloomberg School’s department of biochemistry and molecular biology, said in a press release. “Our study suggests that FUS is part of a class of RNA-binding proteins that facilitate this guiding and targeting.”

“We are interested in using these studies to develop new biomarkers of neurodegenerative disease as well as treatment strategies,” he said.