Scientists Discover How Multiple Sclerosis Kills Brain Cells

A hidden mechanism in MS may be damaging neurons at their genetic core, offering a potential new way to slow the disease.

For many years, research on multiple sclerosis (MS) has centered on myelin, the protective coating around the brain’s nerve fibers. At the same time, another form of damage has received far less attention. Neurons in the cortex, which support thinking and memory, have been steadily dying.

Researchers from UC San Francisco, the University of Cambridge, and Cedars-Sinai Medical Center now report that this loss is linked to DNA damage inside neurons, driven by inflammation in the brain. The discovery helps explain why scans of people with MS show injury not only in white matter, which carries signals, but also in gray matter, where brain cells reside. It also points to new treatment possibilities.

“It’s become clear that in addition to promoting remyelination in progressive MS, it’s essential to find ways to directly protect grey matter neurons themselves,” said Steve Fancy, PhD, DVM, a professor in the UCSF Weill Institute for Neurosciences. He is the co-corresponding author of two papers that appeared April 1 in the same issue of Nature. “We can now point to a mechanism for why these vulnerable neurons in the brain are lost — DNA damage — and begin fighting MS on an entirely new front.”

Understanding White and Gray Matter Damage

Doctors often diagnose MS by identifying lesions in white matter on MRI scans. This tissue consists of nerve fibers that connect different parts of the brain and appears bright on imaging.

Gray matter, which contains the main bodies of brain cells, can also develop lesions, especially near the brain’s surface. These areas are harder to detect but are closely tied to more advanced and disabling forms of the disease.

To better understand this process, the researchers focused on a group of neurons marked by a gene called CUX2. In the first study, they examined how these neurons form in developing mouse brains. This stage of growth places heavy stress on cells as they rapidly divide, spread throughout the brain, and form connections.

During this time, the cells rely on a DNA repair system controlled by a stress-response gene known as ATF4, which helps maintain chromosome stability. When the researchers removed ATF4, the neurons accumulated severe DNA damage, preventing normal development of the frontal brain.

“We saw that just a subset of its neurons were vulnerable to DNA damage,” Fancy said. “And ATF4 is at the center of the strategy for surviving it.”

Inflammation and Breakdown in MS

In the second study, the team detected similar DNA damage in gray matter lesions taken from people with MS, again affecting CUX2 neurons.

Experiments in mouse models showed that inflammation triggered chemical reactions that damaged DNA in these cells. Under these conditions, the repair systems that usually protect neurons during development could not keep up, leading to lasting brain injury.

Together, the findings describe how neurons in the brain’s outer layers normally manage DNA stress and how this protection fails in MS.

“The CUX2 neurons are like a ‘canary in the coal mine’ for the brain affected by MS,” said David Rowitch, MD, PhD, deputy director for Research at Guerin Children’s, professor of Paediatrics at the University of Cambridge, and co-corresponding author. “If we can protect these neurons, we might be able to contain the damage before the disease progresses.”

Reference:

“Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair” by Wenlong Xia, Laura Morcom, Zhaoyang Xu, I-Ling Lu, Qing Wang, Kimberly K. Hoi, Mingming Wei, Keying Zhu, Gregory Jordan, Xiao-Yan Tang, Julio Gonzalez-Maya, Vanesa S. Mattera, Sophia M. Panigrahi, Riki Kawaguchi, Ben Emery, Santos J. Franco, Daniel H. Geschwind, Brian Popko, David H. Rowitch and Stephen P. J. Fancy, 1 April 2026, Nature.
DOI: 10.1038/s41586-026-10290-4

“DNA damage burden causes selective CUX2 neuron loss in neuroinflammation” by Laura Morcom, Wenlong Xia, Zhaoyang Xu, Yashika Awasthi, Celine Geywitz, Matthew O. Ellis, Tomas Noli, Amel Zulji, Daniel Yamamoto, Gemma C. Girdler, Li Kai, Keying Zhu, Mingming Wei, Xiao-Yan Tang, Kimberly K. Hoi, Julio Gonzalez-Maya, Greg J. Duncan, Adrien M. Vaquie, Diana Gold Diaz, Riki Kawaguchi, Erdong Liu, Yu Sun, Denny Yang, Gregory D. Jordan, I-Ling Lu, Staffan Holmqvist, Theresa Bartels, Katherine Ridley, Jennifer Ja-Yoon Choi, Santos J. Franco, Eric J. Huang, Ben Emery, Daniel Geschwind, Lucas Schirmer, Gabriel Balmus, Brian Popko, Stephen P. J. Fancy and David H. Rowitch, 1 April 2026, Nature.
DOI: 10.1038/s41586-026-10310-3

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