Summary: For decades, Multiple Sclerosis (MS) was defined by the destruction of myelin (the brain’s insulation). However, a landmark dual-study reveals a deadlier, quieter process: the death of neurons in the gray matter.
Researchers have traced this loss to a massive breakdown in DNA repair. Specifically, a subset of neurons called CUX2 neurons—the “canaries in the coal mine”—become overwhelmed by inflammation, losing their ability to fix genetic damage. This discovery shifts the focus of MS treatment from just “re-insulating” wires to actively protecting the DNA of the brain’s processing centers.
Key Facts
- The Gray Matter Mystery: While MS is usually diagnosed via white matter lesions (the brain’s “wiring”), it is the damage to gray matter (the “cell bodies”) that often drives chronic disability.
- The CUX2 Vulnerability: Researchers identified CUX2 neurons in the cortex as the most vulnerable to MS. These cells are naturally under high stress from birth and rely on a specific gene, ATF4, to survive.
- DNA Repair Failure: In MS, chronic inflammation sparks chemical reactions that batter the DNA of these neurons. The ATF4-led repair system eventually “breaks,” leading to cell death and cognitive decline.
- A New Therapeutic Front: The findings suggest that “remyelination” (fixing myelin) isn’t enough; future MS drugs must also target DNA protection to prevent the permanent loss of gray matter.
Source: UCSF
For decades, multiple sclerosis research has focused on myelin, the insulation around the brain’s wiring. Scientists paid less attention to another loss that was happening in parallel: neurons in the cortex, the seat of higher thinking and cognition, were quietly dying.
A team led by UC San Francisco, University of Cambridge, and Cedars-Sinai Medical Center now traces that loss to a breakdown in the DNA of neurons as inflammation overwhelms the brain.
The finding helps explain why brain scans of people with MS reveal damage not only to white matter, the brain’s wiring, but also to the brain’s gray matter — and it points to a new direction for the field.
“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.”
MS is typically diagnosed when clinicians see lesions in the myelin-rich white matter of the brain on MRI scans. White matter is made of the nerves that link brain cells and it looks white on a brain scan.
The brain’s grey matter, which houses the “bodies” of the brain cells, can also have MS lesions, especially in its outer layers. These lesions are less common — and harder to see on a brain scan — but they are a sign of chronic and disabling MS.
The scientists wanted to learn more about the neurons that died in these grey-matter lesions, which express a gene called CUX2. In the first study, they looked at developing mouse brains to see how CUX2 neurons are born. This occurs early in life, when the brain is growing quickly, putting cells under tremendous stress.
The cells relied on a mechanism to repair their DNA as they rapidly multiplied, fanned out into the far reaches of the brain and wired up with one another. The mechanism depends on a stress-response gene called ATF4 to keep chromosomes intact. When the team removed ATF4, the growing neurons were rife with DNA damage, and this prevented the frontal part of the brain from forming.
“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.”
In the second study, the team found DNA damage in grey matter lesions from people with MS involving the same neurons.
In mouse models of MS, the researchers saw that inflammation sparked chemical reactions that damaged DNA in CUX2 neurons. The repair systems that protect these neurons from the stresses of development could no longer keep up; and this led to brain damage.
Together, the two studies outline the natural way the brain’s outer layer neurons cope with DNA damage — and how that system breaks down 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.”
Key Questions Answered:
A: We used to think the cells died because their insulation (myelin) was gone. This study shows it’s more direct: the inflammation surrounding the cells actually attacks their DNA. It’s like a house fire that doesn’t just melt the electrical coating but eventually compromises the very foundation of the building.
A: These neurons are born during a period of intense brain growth, meaning they are “high-performance” cells that are used to working under pressure. Because they are so active in the cortex (the seat of higher thought), they have a high metabolic demand. When MS-related inflammation hits, they simply “burn out” their DNA repair systems faster than other cells.
A: Not at all—current treatments are great at reducing inflammation and protecting white matter. However, this explains why some patients still decline even when their “wiring” looks okay on a scan. This research provides the “missing link” for developing a second class of drugs that shield the DNA of our most important thinking cells.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this multiple sclerosis research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image: The image is credited to Neuroscience News
Original Research: Open access.
“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 & David H. Rowitch. Nature
DOI:10.1038/s41586-026-10310-3
Abstract
DNA damage burden causes selective CUX2 neuron loss in neuroinflammation
Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease, but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood.
Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2 and layer 3 (L2/3) excitatory neurons (L2/3ENs) that express CUT-like homeobox 2 (CUX2) are selectively vulnerable to degeneration.
Here we report that L2/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs were recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability.
Functions of Cux2 and activating transcription factor 4 (Atf4) were essential for resilience of L2/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis, was sufficient to elevate levels of reactive oxygen species, leading to DNA damage-mediated neuronal death in vitro, and caused selective depletion of L2/3 neurons in mice.
These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3ENs contributes to selective vulnerability in neuroinflammatory injury.
