When Repair Fails: Why Neurons Die in Multiple Sclerosis

The study investigated how neurons die in multiple sclerosis and found that the accumulation of DNA damage plays a key role in this process. By analyzing human tissues and experimental models, researchers identified that certain neurons are especially vulnerable because they exhibit a higher damage burden and lower repair capacity. Furthermore, the inflammation typical of the disease intensifies this damage, leading to cell death. The results suggest that therapies focused on protecting DNA or improving its repair may be promising strategies in the treatment of the disease.

Multiple sclerosis is a complex neurological disease that primarily affects young adults and can lead to the progressive loss of cognitive and motor functions. Although traditionally understood as an autoimmune disease that attacks myelin, the protective layer of neurons, more recent research shows that the problem goes beyond that.

The direct loss of neurons also plays an important role in the progression of the disease. This study seeks to understand exactly how these neurons die, focusing on a central element of cellular biology: DNA damage.

Within each cell of our body, DNA functions as an essential instruction manual for proper functioning. However, this genetic material is constantly being damaged. This damage can arise from natural processes within the organism itself, such as cellular metabolism, which generates unstable molecules called reactive oxygen species, or even during normal activities such as reading and copying DNA.

Furthermore, external factors such as pollution, radiation, and diet also contribute to these lesions. When DNA is damaged, the cell needs to repair these errors quickly. Otherwise, it can compromise its function and eventually lead to cell death.

Neurons possess sophisticated mechanisms to detect and repair DNA damage. This set of processes is called the DNA damage response. There are different repair systems, each specialized in correcting specific types of lesions.

Some correct small, localized damage, while others deal with more serious breaks in the DNA structure. These mechanisms are essential for maintaining genetic stability and ensuring the survival of neurons, which are particularly sensitive cells and generally do not regenerate easily.

Researchers focused their attention on a specific type of neuron located in the outermost layers of the cerebral cortex. These neurons are important for higher cognitive functions, such as thinking and perception.

Previous studies had already shown that they are especially vulnerable in multiple sclerosis, but the reason was unclear. In this study, scientists investigated whether this vulnerability could be related to a higher burden of DNA damage or a reduced capacity for repair.

To answer these questions, the researchers used a combination of approaches. First, they analyzed brain tissue from people with multiple sclerosis, directly observing the affected neurons. They identified elevated signs of DNA damage in these specific neurons.

Lesions caused by multiple sclerosis. Image: Paul M Matthews et al. https://doi.org/10.1136/practneurol-2016-001381

Next, they used experimental mouse models to reproduce conditions similar to the disease, such as brain inflammation and myelin loss. These models allowed them to observe, in a controlled manner, how neurons responded to inflammatory stress. This indicated that the ability to repair is a crucial factor for cell survival.

Another important point investigated was the influence of the immune system. In multiple sclerosis, there is an intense inflammatory response in the brain. The researchers showed that a specific inflammatory molecule, known to participate in the disease, can increase the production of toxic substances within cells.

These substances cause more damage to DNA, creating a harmful cycle: more inflammation leads to more damage, which in turn leads to the death of neurons. Laboratory experiments confirmed that this molecule alone is already capable of inducing neuronal death through this mechanism.

In developing mice, CUX2 neurons, which lack a DNA repair enzyme, succumb to DNA damage. The cells are shown in blue; the DNA damage in green; and the dying cells in red. The same neurons die in multiple sclerosis, as the inflammation caused by the disease causes severe DNA damage. Credit: Fancy Lab / UCSF

The study revealed that certain neurons are more vulnerable because they accumulate more DNA damage and are unable to repair it efficiently. This combination of high exposure to damage and low recovery capacity makes them particularly susceptible to death in inflammatory environments.

Furthermore, improving repair mechanisms has been shown to increase the survival of these cells, suggesting a possible therapeutic avenue.

These findings change how we understand multiple sclerosis. Instead of being just a disease affecting myelin, it also directly involves the genetic integrity of neurons. DNA damage emerges as a central factor in neuronal degeneration, especially in contexts of chronic inflammation.

Understanding these mechanisms opens new possibilities for the development of treatments that protect neurons, not only by controlling inflammation but also by strengthening cellular repair systems.

READ MORE:

DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

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

Nature. 1 April 2026DOI: 10.1038/s41586-026-10310-3

Abstract:

Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, 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 degeneration2. 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 pathogenesis3,4, 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.