ALS research often focusses on motor neurons: the nerve cells that control muscle movement and gradually degenerate in people with ALS. Increasingly, however, researchersare finding that the immune system also plays an important role in the development of the disease. “ALS is like a bucket with multiple holes. The immune system is one of those holes that we need to patch,” explains researcher Marta Canizares Luna. For several years, she investigated how genetic changes in the ATXN2 gene contribute to ALS. On June 10, she will defend her PhD thesis.
Genetic variations in the ATXN2 gene are considered a risk factor for ALS. This means that carrying such a variation, together with other genetic factors and environmental influences, increases the likelihood of developing the disease. However, we still don’t clearly understand how mutations in the ATXN2 gene actually raise the risk of developing ALS.
Marta and her colleagues at UMC Utrecht found that this genetic change disrupts normal processes in cells. ‘To our great surprise, we discovered that the altered ATXN2 gene affects thebrain’s immune system.’ They also observed that motor neurons of people with an abnormal ATXN2 gene have greater difficulty coping with stress: harmful influences from outside or inside the cell. These processes can ultimately lead to damage to nerve cells.
To understand why this happens, Marta looked at microglia in ALS mouse models that carry ATXN2 mutations. Microglia are specialized immune cells in the brain and spinal cord thathelp remove waste and maintain a healthy nervous system. She discovered that microglia in affected mice differed from healthy microglia in both shape and gene activity. The samealterations were also observed in brain organoids derived from ALS patients carrying ATXN2 mutations, small laboratory-grown models of the human brain.
“Even before clear changes become visible in motor neurons, we already see alterations in the immune system in ALS mice that carry ATXN2 mutations,” Marta explains. “We believe theimmune system contributes to the degenerative process by making motor neurons more vulnerable. Changes in the ATXN2 gene appear to impair the ability of microglia to support motor neurons, leaving these cells less resilient to stress and more likely to die.”
The ATXN2 gene contains a repeated sequence that in healthy individuals is rather short, and helps ATXN2 fulfill its normal functions, particularly important when cells are under stress. However, some ALS patients carry more repeated sequences in ATXN2, which disrupts the normal functions of the protein, affecting how ATXN2 interacts with other components of thecell.
Marta and her colleagues found that this disturbance also increases the vulnerability of motor neurons to stress, potentially accelerating their degeneration. Before this study, it was lesswell understood how the extended sequences in ATXN2 contribute to the development of ALS and which cells within the brain and spinal cord are more affected by it.
Previous studies have shown that reducing ATXN2 protein levels can lessen disease severity in ALS mouse models. Marta’s findings suggest that the immune system may play a key rolein this effect. Importantly, these insights may be relevant not only for people who carry an ATXN2 variation. Lowering ATXN2 levels could potentially slow disease progression in peoplewith ALS who do not have this genetic change, by improving the overall support that the immune system provides to motor neurons.
“We now have a better understanding of why ATXN2 is a risk factor for ALS. At the same time, many pieces of the puzzle are still missing.” Several other research projects at the ALS Center in the UMC Utrecht are also investigating the role of the immune system in ALS. By studying neurodegeneration from different perspectives, researchers hope to uncover new therapeutic strategies.“ Perhaps in the future we can develop treatments that provide better support to motor neurons and help compensate for the effects of a dysfunctional immune system,” Marta says.
