UMC Utrecht research sheds new light on ALS risk gene

UMC Utrecht research sheds new light on ALS risk gene

The research group of Professor Jeroen Pasterkamp, Professor of Translational Neuroscience and Scientific Director of the UMC Utrecht Brain Center, has investigated a genetic mutation that can cause ALS. The study reveals what exactly goes wrong in the cells of ALS patients who carry this mutation. The findings have been published in the renowned scientific journal Nature Communications.

ALS (amyotrophic lateral sclerosis) is a progressive neurological disease that leads to the gradual degeneration of motor neurons in the brain and spinal cord. As a result, patients slowly lose the ability to move, speak, swallow, and eventually breathe. Worldwide, ALS affects approximately 2 in 100,000 people each year. In the Netherlands, about 500 people are diagnosed annually. Most patients die within three to five years after the first symptoms appear.

Previous research has shown that a repeat expansion—a specific lengthening of a piece of DNA—in the ATXN2 gene is present in nearly 5% of ALS patients, making it one of the strongest known genetic risk factors for the disease. The research by Pasterkamp’s group aimed to uncover what happens inside cells when someone carries this DNA expansion.

Less cellular energy

The researchers used mouse models, as well as nerve cells and brain organoids derived from ALS patient cells, comparing them to those made from healthy donor cells. The results were striking: nerve cells with the DNA expansion showed damage in their axons (cell extensions) and altered metabolism. Notably, the affected cells produced less energy.

The team also crossbred mice carrying the DNA expansion with mice already genetically predisposed to ALS. Professor Pasterkamp explains:
“We observed that ALS symptoms appeared earlier and were more severe in these combined mice. This suggests that the ATXN2 repeat expansion can accelerate ALS disease progression.”

New insights

One of the most important findings of the study was that the ATXN2 repeat expansion not only affected nerve cells but also had an impact on immune cells in the brain, specifically microglia. Pasterkamp elaborates:
“These cells normally help clear waste from the brain, but in our model, they functioned less effectively. This impaired function may contribute to worsening ALS symptoms.”

The research provides new insights into how genetic factors can increase the risk of ALS. By better understanding how this specific DNA expansion contributes to the disease, scientists can more effectively search for ways to slow down or correct these processes—potentially leading to new treatments for ALS patients.

Although the findings are promising, Professor Pasterkamp emphasizes that further research is needed:
“It’s not yet fully understood how this genetic alteration causes the effects we observed,” he says. “We hope our work will ultimately contribute to the development of new therapies targeting the ATXN2 repeat expansion or its downstream effects.”

Source: UMC Utrecht