Scientists take key step toward unraveling the genetic roots of ALS in a pair of studies

If you shrunk down for a “Magic School Bus”-style journey into an ALS patient’s neurons, you’d see the same thing nearly every time — a key protein knotted into clumps and missing from its usual post in the cell’s nucleus.

It’s a telltale sign of the devastating neurological disease, and its effects have been a longtime subject of fascination for scientists. Now, a pair of studies published Wednesday help unravel the mystery.

Researchers found that defects in a molecule that processes and preps RNA causes cells to churn out faulty versions of UNC13A, a protein that influences how neurons signal one another. Genetic variants in UNC13A associated with ALS exacerbate the issue, as patients with more copies of these variants tend to have higher levels of defective protein and shorter survival times.

Teams led by scientists at Stanford and University College London made essentially the same discovery at the same time, with both reports published simultaneously in the journal Nature. Their findings suggest that correcting protein production in ALS patients could be a useful treatment strategy, though researchers will first need to figure out how many proteins they need to target and the best way to do so.

“This discovery tells us a lot about how the disease works. And it puts a path towards designing a therapy and testing it,” said Aaron Gitler, a Stanford geneticist and senior author of one of the studies. “But there’s still a long way to go.”

There’s currently no cure for amyotrophic lateral sclerosis, a fatal disease estimated to affect about 5 out of every 100,000 people in the United States. In ALS, neurons in the brain and spinal cord that control parts of your body, including your arms and legs, stop working and die. At first, that can make it hard to walk or run. That’s what forced baseball icon Lou Gehrig to retire in 1939. (ALS is also known as Lou Gehrig’s disease).

In time, chest muscles that control breathing fail, too. Most ALS patients die within two to five years after diagnosis, usually due to respiratory failure.

In nearly all patients, neurons in the brain and spinal cord differ from those in people without the disease in an unmistakable way: with those knotty clumps of protein.

That protein, TDP-43, latches onto messenger RNA and regulates which bits of genetic code get used for protein production. You can think of this step like editing an essay. Keep one paragraph and scrap another, and your story now reads a bit differently. The same is true with proteins, with so-called alternative splicing producing multiple versions of a protein, each of which behaves slightly differently.

Gitler’s team, which has spent 15 years studying TDP-43, went hunting for examples of splicing errors linked to ALS that could play a key role in disease. Researchers had already found one such example, and, in the recent study, the Stanford group sifted through publicly available data in search of others.

They found 66 genes that were spliced differently in patients with ALS. One of them, UNC13A, immediately caught Gitler’s eye. That’s because the protein, which regulates how neurons send chemical signals to one another, had been linked to ALS in previous genetic studies. The authors found that UNC13A RNA in ALS patients included an extra stretch of genetic sequence. This sequence only showed up in cells missing TDP-43 from their nucleus, suggesting that the protein ordinarily helps snip out this region.

Splicing errors were even more frequent among patients with genetic variants of UNC13A associated with a higher risk of ALS. Rosa Ma, a graduate student in Gitler’s lab, found that these variants, known as single nucleotide polymorphisms, weren’t just in any random part of UNC13A — they were in or near the site of the error. And patients with two copies of the variants died more quickly after diagnosis than those with one or none.

“Shoot, that’s going to be big,” Gitler recalls blurting when he saw Ma’s finding. “It’s screaming at you that this is important, because it’s proven through human genetics.”

(“Shoot” may not have been his exact word, Gitler acknowledged. But it’s close.)

Meanwhile, a group at University College London was making nearly the exact same discovery. Once the two teams learned of each other’s progress, they struck an unorthodox pact: They uploaded their papers to preprint server bioRxiv — meaning they had not yet been peer-reviewed — at exactly the same time before submitting to Nature, where they continued to coordinate their progress.

“Too much emphasis is unfortunately put on being the first at publishing results, and therefore, initially, knowing another team was working on the same results did cause some anxiety,” Pietro Fratta, senior author of the U.K. group’s study, said in an email. “Truth is, it’s really exciting we both came to the same conclusions, and this really supports the science underlying it.”

Researchers are now exploring how they can turn their discovery into an ALS treatment. One way to do so could be with a short snippet of genetic code that binds to messenger RNA and prevents or corrects UNC13A splicing defects. That’s the idea behind Spinraza, a blockbuster drug for spinal muscular atrophy, a debilitating neuromuscular disease.

But it’s unclear whether targeting UNC13A alone would help, or whether researchers would need to target a whole slew of splicing errors. Gitler’s team is just starting to tackle that question.

Still, the studies are raising hopes among ALS experts who stress that approved, effective treatments for the disease are sorely needed. The Food and Drug Administration is currently reviewing a drug application from Amylyx Pharmaceuticals, but there’s no guarantee the biotech’s treatment will be approved. And BrainStorm Cell Therapeutics has yet to apply for approval of its ALS drug after the FDA raised concerns last year about the company’s clinical trial results.

“I think [this study’s] beginning to form sort of a new perspective on the disease,” said Sam Pfaff, a neuroscientist at the Salk Institute who was not part of either recent report. “This serves as a nice reference point to begin to think much more seriously about splicing and trying to treat the defects that might arise.”

Correction: An earlier version of this story incorrectly stated that BrainStorm Cell Therapeutics had submitted an application for its experimental ALS drug to the FDA.