We may finally know how a mutated gene creates the toxic proteins of ALS

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A tough puzzle to solve. (Robina Weermeijer on Unsplash/)

We've known for a while that having a mutation in one specific gene is the most common genetic cause of ALS, also known as Lou Gehrig's disease. What we didn't know is how that miscoded DNA turns into illness.

People with this mutation have hundreds of extra copies of a short RNA sequence—GGGGCC. Most people just have a few copies, says Aaron Gitler, a geneticist at Stanford University who is one of the authors of a new study out today in Nature Neuroscience. In those people, the sequence doesn't do anything; it just sits there as part of the genome, known as the gene RPS25. But in people with hundreds of copies, the sequence comes alive and codes for a protein that damages neurons as it builds up. How exactly that happened has been mysterious—until now.

“What we set out to do is discover how that protein works,” Gitler says. The team started with yeast, which is easy to do genetic modifications on. When they turned down the activity of RPS25, they found, they could lower the yeast’s production of those dangerous proteins by half.

Without RPS25, Gitler says, the yeast were fine, “but they couldn’t make these aberrant proteins.”

The researchers were able to do the same thing to fruit flies (another organism with genes that are relatively easy to manipulate) and then again in lab-grown human neurons. They even found similar effects in human cells with the genetic profile for two other neurodegenerative diseases also characterized by protein buildup.

This discovery “gives us a toehold to learn about how this process works,” Gitler says. But it’s just the beginning of a much bigger process. He compares knowing about the function of RPS25 to having a puzzle piece, but not knowing where it fits in the puzzle.

Understanding if the gene RPS25 is even necessary for normal protein production would be akin to figuring out that puzzle piece placement. If people can live without RPS25, we might be able to translate these scientific advances into clinical therapies for ALS. Testing whether or not mice need RPS25 to stay healthy is the next step.

But at this point, Gitler cautions, what the team has is a basic scientific discovery. “We’re a few steps away from translating it in humans.”

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Written By Kat Eschner