For decades, multiple sclerosis research has focused on myelin, the insulation around the brain’s wiring. Scientists paid less attention to other losses occurring in parallel. Neurons in the cortex, the seat of higher-level thinking and cognition, were silently dying.
A research team led by the University of California, San Francisco, the University of Cambridge, and Cedars-Sinai Medical Center has now determined that the loss is caused by destruction of neurons’ DNA when inflammation overwhelms the brain. The findings help explain why brain scans of MS patients reveal damage to not only the white matter, but also the gray matter, the brain’s wiring, and points to a new direction for the field.
“It has become clear that in addition to promoting remyelination in progressive MS, it is essential to find ways to directly protect gray matter neurons themselves,” said Steve Fancy, DVM, of the UCSF Weill Institute for Neuroscience. He is co-corresponding author of two papers published in the same issue on April 1. nature. “We can now point to the mechanism of DNA damage – why these vulnerable neurons in the brain are lost – and begin to fight MS on a whole new front.”
MS is usually diagnosed when a clinician sees lesions in the myelin-rich white matter of the brain on an MRI scan. White matter is made of nerves that connect brain cells and appears white on brain scans.
The brain’s gray matter, which houses the “main body” of brain cells, can also have MS lesions, especially in its outer layers. These lesions are less common and difficult to see on brain scans, but they are a sign of chronic and disabling MS.
The scientists wanted to learn more about the neurons that died in these gray matter lesions, which express a gene called CUX2. The first study looked at mouse brain development to see how CUX2 neurons are born. This occurs early in life when the brain is growing rapidly and puts a lot of stress on the cells.
The cells relied on DNA repair mechanisms to rapidly proliferate, spread far into the brain, and connect with each other. This mechanism relies on a stress-responsive gene called ATF4 to keep chromosomes intact. When the researchers removed ATF4, the growing neurons developed massive amounts of DNA damage, which disrupted the formation of the front part of the brain.
They found that only a subset of neurons were susceptible to DNA damage. And ATF4 is at the center of the strategy to survive it. ”
Dr. Steve Fancy, DVM, Professor, UCSF Weill Neuroscience Institute
In the second study, the research team found DNA damage in gray matter lesions in MS patients involving the same neurons.
In a mouse model of MS, researchers confirmed that inflammation triggers a chemical reaction that damages the DNA of CUX2 neurons. The repair systems that protect these neurons from developmental stress can no longer be maintained. And this led to brain damage.
Together, the two studies outline how neurons in the brain’s outer layers naturally cope with DNA damage and how that system malfunctions in MS.
“CUX2 neurons are the ‘canary in the coal mine’ for brains affected by MS,” said co-corresponding author David Lowwich, MD, associate director of research at Guerin Children’s Hospital, professor of pediatrics at the University of Cambridge. “If we can protect these neurons, we may be able to limit the damage before the disease progresses.”
sauce:
University of California, San Francisco
Reference magazines:
Morcombe, L. and others. (2026). DNA damage load causes selective CUX2 neuron loss in neuroinflammation. Nature. DOI: 10.1038/s41586-026-10310-3. https://www.nature.com/articles/s41586-026-10310-3
