Scientific Breakthrough Links Multiple Sclerosis Neuron Death to Overwhelming DNA Damage in Brain’s Grey Matter

UCSF scientists find that Multiple Sclerosis kills grey matter neurons by overwhelming DNA repair systems, pointing to new ways to protect cognitive function.

By: AXL Media

Published: Apr 1, 2026, 11:07 AM EDT

Source: Information for this report was sourced from University of California - San Francisco

Shifting the Pathological Focus From Myelin to Grey Matter

For decades, the scientific community has primarily viewed Multiple Sclerosis as a disease defined by the destruction of myelin, the protective insulation surrounding the brain’s wiring. However, a landmark collaborative study led by UC San Francisco, the University of Cambridge, and Cedars-Sinai Medical Center has revealed that the death of neurons in the cerebral cortex occurs in parallel to myelin loss. This research provides a long-awaited explanation for why patients often exhibit significant damage to grey matter, which serves as the seat of higher thinking and cognitive function. By identifying that these essential neurons are quietly dying due to internal cellular failures, the study opens a new front in the fight against progressive neurological decline.

The Vulnerability of CUX2 Neurons to Oxidative Stress

The investigation specifically highlighted a subset of cells known as CUX2 neurons, which appear uniquely susceptible to the rigors of both development and disease. According to Steve Fancy, a professor at the UCSF Weill Institute for Neurosciences, these neurons are located in the outer layers of the cortex and are frequently lost in the grey-matter lesions associated with chronic MS. The research suggests that these cells act as a biological indicator of disease severity. When inflammation overwhelms the brain, it sparks chemical reactions that directly assault the genetic integrity of these specific neurons, leading to their eventual death and the subsequent cognitive impairment observed in long-term patients.

The Critical Role of the ATF4 Repair Mechanism

In a foundational component of the research involving mouse models, scientists discovered that the survival of these neurons depends on a stress-response gene called ATF4. During early brain development, CUX2 neurons multiply and wire the frontal part of the brain under intense physiological pressure, relying on ATF4 to keep their chromosomes intact. The study demonstrated that when this gene is absent or suppressed, neurons become riddled with DNA damage and fail to form properly. This same mechanism appears to be the point of failure in adult Multiple Sclerosis, where the repair systems that once protected the brain during its growth phase are no longer able to keep pace with disease-driven inflammation.