Scientists Uncover Key Brain Cells Most at Risk of Damage in Multiple Sclerosis

BYLINE: Shishira Sreenivas

Newswise — LOS ANGELES (April 1, 2026) — A multicenter team of investigators from Cedars-Sinai Guerin Children’s, the University of California, San Francisco (UCSF), and the University of Cambridge in the United Kingdom, has identified critical neurons in the gray matter, the “thinking” portion of the brain, that are especially prone to DNA damage as neurological disease-related inflammation progresses.

The findings, stemming from two complementary studies published in Nature, could lead to therapies to protect the brain in neurological conditions like multiple sclerosis (MS).

Investigators focused on a group of brain cells called “CUX2 neurons.” Located on the outer layer of the brain, known as the cortex, CUX2 neurons are linked to brain communication, movement, thinking and memory. They are also linked to many neurological conditions, including MS, autism, epilepsy and Alzheimer’s disease.

In the first study, researchers found that CUX2 neurons are especially sensitive to damage caused by inflammation. In diseases like MS, the body’s immune system attacks the brain, leading to long-term damage. While MS has been thought to primarily affect white matter in the brain, this research shows that it could also damage particularly vulnerable CUX2 neurons in the gray matter.

This damage may help explain why people with MS can experience memory problems and cognitive decline as the disease progresses.

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

To better understand the workings of CUX2 neurons, investigators performed genetic sequencing of brain tissue from people with MS, and in laboratory mice that can model MS. Their study concluded that these neurons, when under stress, sustain much more DNA damage than neighboring brain cells do. Over time, this damage can lead to cell death.

In the second study, investigators found that CUX2 neurons use the molecule ATF4 to help repair their DNA. ATF4 and the molecules it regulates act like a switch that turns on genes that protect critical brain cells from DNA damage.

Even with these repair tools, the study found, CUX2 neurons remain at risk, especially during long-term inflammation. This may be one reason the condition of people with progressive MS continues to worsen even when treatments reduce inflammation.

“We were excited to find that these brain cells already have natural ways to repair themselves,” said Stephen Fancy, PhD, DVM, co-corresponding author of the study and professor in the departments of Neurology and Pediatrics at UCSF. “By uncovering how certain brain cells protect and repair themselves, we have taken a significant step toward developing treatments that could one day preserve brain function and quality of life.”

Through the studies, researchers found that there are several ways to switch on protective processes in the body that can help prevent damage. Further research is needed to bring the findings into clinical use, but they represent a step toward new approaches to treating brain diseases—one that focuses on limiting DNA damage, enhancing repair and bolstering the resilience of critical brain cells.

“Findings from these two studies represent an important milestone in our understanding of neurological disease pathways,” said Nancy Sicotte, MD, chair of the Department of Neurology and director of Multiple Sclerosis and Neuroimmunology at Cedars-Sinai. “This work is a testament to the dedication and innovation of our investigators, who continue to push the boundaries of science and drive discovery in pursuit of effective therapies for patients.”

Other authors who contributed to the first study include: Laura Morcom, Wenlong Xia, Zhaoyang Xu, Yashika Awasthi, Celine Geywitz, Matthew Ellis, Tomas Noli, Amel Zulji, Daniel Yamamoto, Gemma Girdler, Li Kai, Keying Zhu, Mingming Wei, Xiao-Yan Tang, Kimberly Hoi, Julio Gonzalez, Greg Duncan, Adrien Vaquie, Diana Gold, Riki Kawaguchi, Erdong Liu, Yu Sun, Denny Yang, Gregory Jordan, I-ling Lu, Staffan Holmqvist, Theresa Bartels, Katherine Ridley, Jennifer Choi, Santos Franco, Eric Huang, Ben Emery, Daniel Geschwind, Lucas Schirmer, Gabriel Balmus and Brian Popko.

Funding for the first study: This work was supported by funding from the European Research Council (Advanced Grant 789054 to D.H.R.; DecOmPress ERC StG, 950584 to L.S.), the Wellcome Trust (to D.H.R.), NIH (P01 NS083513 to D.H.R. and S.P.J.F.; R01NS128021 and R21NS133891 to S.P.J.F.; R01 NS124166 to S.J.F.; R01NS120981 to B.E.; 1R35NS137478 to B.P.), NIHR Cambridge Biomedical Research Centre (NIHR203312 to D.H.R.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.H.R., D.G. and B.P.), the US Department of Defence (MS230141 to S.P.J.F.), Alex’s Lemonade Stand Foundation (to S.P.J.F.), Race to Erase MS (to S.P.J.F.), the National MS Society (RFA-2203-39300 to L.S.; RG-2001-35775 to B.E.), the German Research Foundation (InCheck GRK 2727, Priority Program SPP 2395, NeuroFlame FOR 5705 to L.S.), the UK Dementia Research Institute (to G.B.), Therapeutic Innovation Networks (PNRR-III-C9-2022-I8 to G.B.), the Hertie Foundation (medMS MyLab, P1180016 to L.S.), an endowment from the Warren family (to B.E.), and a gift from the Spangler Foundation (to S.P.J.F.).

Other authors who contributed to the second study include: Wenlong Xia, Laura Morcom, Zhaoyang Xu, I-Ling Lu, Qing Wang, Kimberly Hoi, Mingming Wei, Keying Zhu, Gregory Jordan, Xiao-Yan Tang, Julio Gonzalez, Vanesa Mattera, Sophia Panigrahi, Riki Kawaguchi, Ben Emery, Santos Franco, Daniel Geschwind and Brian Popko.

Funding for the second study: This work was supported by funding from the European Research Council Advanced Grant (789054 to D.H.R.), the Wellcome Trust (to D.H.R), NIH (P01 NS083513 to D.H.R., S.P.J.F; and R35 NS137478 to B.P.) and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to D.H.R., D. G, B. P.), and the NIHR Cambridge Biomedical Research Centre (NIHR203312). This work was supported by the NIH NINDS (R01 NS128021 and R21 NS133891 to S.P.J.F.), the U.S. Department of Defence (MS230141 to S.P.J.F.), Alex’s Lemonade Stand Foundation (to S.P.J.F.), Race to Erase MS (to S.P.J.F.), and a generous gift from the Spangler Foundation (to S.P.J.F.).

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