Scientists discover a key function of ALS-linked protein

March 8, 2018, Johns Hopkins University Bloomberg School of Public Health
An MRI with increased signal in the posterior part of the internal capsule which can be tracked to the motor cortex consistent with the diagnosis of ALS. Credit: Frank Gaillard/Wikipedia

The protein FUS, whose mutation or disruption causes many cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), works as a central component of one of the most important regulatory systems in cells, according to a new study in Molecular Cell from scientists at Johns Hopkins Bloomberg School of Public Health.

Precisely what FUS does in and why its dysfunction causes the deaths of neurons in ALS and FTD has long been a mystery. The scientists found evidence, though, that FUS is a key part of a system called the microRNA-mediated gene silencing system, which fine-tunes cellular activity by blocking the translation of certain into proteins.

"Thousands of microRNAs work in cells as part of this system, so our findings suggest that the disruption of FUS could lead to widespread failures of normal gene-expression regulation, which in turn could contribute to the development of these ," says study senior author Jiou Wang, MD, PhD, associate professor in the Bloomberg School's Department of Biochemistry and Molecular Biology. "Knowing how these diseases arise should of course be helpful in devising strategies to treat them."

ALS, which affects about 30,000 Americans at any one time, features the degeneration of muscle-controlling neurons in the brain and the spinal cord, ultimately leading to respiratory failure. Most patients die within a few years of the first appearance of symptoms. FTD is the second most common dementia after Alzheimer's disease in people younger than 65, and primarily involves the degeneration of frontal and temporal lobe neurons, with associated disruptions to cognitive and executive functions. It progresses to profound dementia and immobility and usually is fatal within a decade of diagnosis.

Researchers first linked inherited FUS mutations to subsets of ALS and FTD cases in 2009. Since then, studies have found that even when it is not mutated, the often exists in abnormal clumps outside the cell nucleus where it normally works. That suggests its disruption is a common event in the disease process.

Knowing what FUS normally does in cells should provide clues to how ALS and FTD originate. FUS is an RNA- and DNA-binding protein and works mainly in the cell nucleus. It has been shown to be involved in repairing DNA damage. It also has been linked to the regulation of gene expression—disrupting FUS causes changes in the levels of some microRNAs, small RNA molecules that help regulate whether genes get translated into proteins. But the protein's full set of functions and how they relate to ALS and FTD have never been clear.

Wang and his colleagues began their study with the discovery that FUS binds to a protein called Argonaute2, a member of the Argonaute family of proteins. Argonautes are a key part of the microRNA gene silencing system in cells. The microRNAs guide Argonautes to specific targets, the RNA transcripts of genes—called messenger-RNAs—which ordinarily would be translated into proteins. The Argonautes destroy these messenger-RNA targets, typically by cutting them in two. The system is an important regulator of the activities of cells, meant to keep them healthy and working amid fast-changing conditions and stresses. The finding that FUS associates with a key Argonaute protein suggested to Wang and his team that it too may be an important and central part of this system.

In further experiments, the scientists showed that removing FUS from cells, or replacing it with a mutant, ALS-linked version, dramatically reduces the silencing activity of several microRNAs whose targets are suspected of contributing to ALS. The impact on microRNAs was likely much broader than that, though, for the researchers observed changes in the levels of hundreds of gene transcripts. Many of the more-altered ones are known to be involved in important brain processes, hinting that there could be a strong impact on brain cells.

The team showed that an evolutionarily distant version of FUS exists in the roundworm C. elegans, a much-studied lab animal, where it is required for maximizing the efficiency of microRNA-mediated gene silencing. They concluded from their experiments that FUS has this role in mammals too, and accomplishes it as a helper protein that interacts with Argonaute2, microRNAs, and the microRNAs' messenger-RNA targets.

"It is thought to be a challenge for Argonaute proteins and microRNAs to find messenger-RNA targets efficiently," Wang says. "Our study suggests that FUS is part of a class of RNA-binding proteins that facilitate this guiding and targeting."

That in turn suggests—and indeed the study's results directly show—that a disruption of FUS such as an ALS-linked mutation will impair the microRNA-based regulation of a large number of genes. Although the precise reasons for the deaths of neurons in ALS and FTD aren't yet clear, the affected cells might be those that are especially vulnerable to this particular type of large-scale gene dysregulation.

Wang and colleagues are now doing further studies to determine whether there are other RNA-binding proteins that have this same microRNA-helper function. If so, they may be relevant to ALS and other neurodegenerative diseases.

"We are interested in using these studies to develop new biomarkers of neurodegenerative disease as well as treatment strategies," Wang says.

Explore further: Choreographing the microRNA-target dance

More information: "FUS Regulates Activity of MicroRNA-Mediated Gene Silencing"Molecular Cell (2018).

Related Stories

Choreographing the microRNA-target dance

January 23, 2017
Scientists face a conundrum in their quest to understand how microRNAs regulate genes and therefore how they influence human disease at the molecular level: How do these tiny RNA molecules find their partners, called messenger ...

Witnessing the birth of a tiny RNA at brain synapses

February 13, 2017
Proteins are the building blocks of all cells. They are made from messenger RNA (mRNA) molecules, which are copied from DNA in the nuclei of cells. All cells, including brain cells regulate the amount and kind of proteins ...

Recommended for you

Team seeks to create genetic map of worm's nervous system

December 10, 2018
How do you build a brain? What "rules" govern where neurons end up, how they connect to each other, and which functions they perform?

Genetic study of epilepsy points to potential new therapies

December 10, 2018
The largest study of its kind, led by international researchers including scientists at RCSI (Royal College of Surgeons in Ireland), has discovered 11 new genes associated with epilepsy.

Classifying brain microglia: Which are good and which are bad?

December 6, 2018
Microglia are known to be important to brain function. The immune cells have been found to protect the brain from injury and infection and are critical during brain development, helping circuits wire properly. They also seem ...

Drawing is better than writing for memory retention

December 6, 2018
Older adults who take up drawing could enhance their memory, according to a new study.

Friend or foe? Brain area that controls social memory also triggers aggression

December 5, 2018
Columbia scientists have identified a brain region that helps tell an animal when to attack an intruder and when to accept it into its home. This brain area, called CA2, is part of the hippocampus, a larger brain structure ...

How the brain hears and fears

December 5, 2018
How is it that a sound can send a chill down your spine? By observing individual brain cells of mice, scientists at Cold Spring Harbor Laboratory (CSHL) are understanding how a sound can incite fear.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.