DNA Damage Outpaces Repair in Inflammation: New Insights for Multiple Sclerosis Treatments

Brain cells critical to human cognition and thinking are uniquely vulnerable to the progressive damage caused by multiple sclerosis (MS), according to new research published April 1 in the journal Nature. Scientists have identified a previously underexplored mechanism: inflammation-driven DNA damage in these neurons outpaces their ability to repair themselves, leading to cell death and cognitive decline. The discovery could open new avenues for treating the progressive phase of MS, which currently lacks effective therapies for brain shrinkage and mental impairment.

For decades, MS research has focused on the loss of myelin, the fatty insulation around nerve fibers that allows for rapid communication between brain cells. While this damage is well understood and contributes to the muscle weakness, tingling, and pain associated with MS, a second, more insidious process has gone largely unaddressed: the death of neurons in the brain’s cortex, the outer layer responsible for higher thinking, cognition, and computation.

The new studies, led by researchers at the University of Cambridge, University of California, San Francisco (UCSF), and Cedars-Sinai Medical Center, pinpoint a specific group of neurons called CUX2 neurons. These cells are vital for human cognitive functions and are particularly prone to degeneration in progressive MS. During brain development, CUX2 neurons multiply rapidly, which increases their risk of accumulating DNA damage. A protein called ATF4 plays a crucial role in jump-starting the DNA repair process in these cells, helping them survive the stresses of rapid growth.

When researchers switched off ATF4 in mice, CUX2 neurons in their brains quickly died, demonstrating the critical role of this repair mechanism. In human brain tissue from individuals with MS, the layers where CUX2 neurons reside showed significantly higher levels of DNA damage compared to healthy brains. Similarly, in mice engineered to develop an MS-like condition, CUX2 neurons died due to DNA damage triggered by inflammation.

The findings suggest that the DNA damage these neurons experience during development may leave them more vulnerable later in life. When inflammation from MS overwhelms their already compromised repair systems, the result is cell death and the cognitive decline seen in progressive MS.

“There’s no treatment really for that part,” says Steve Fancy, a neuroscientist at UCSF and co-corresponding author of the studies. “But now we can 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.”

Current MS treatments primarily target inflammation caused by the immune system. While these therapies have been successful in slowing myelin loss, they do little to address the progressive damage to gray matter and the resulting cognitive decline. The new research highlights the need to develop treatments that directly protect neurons from DNA damage, potentially offering a new direction for MS therapy.

David Rowitch, a developmental neuroscientist at the University of Cambridge, emphasizes the importance of this discovery: “By better understanding how MS kills brain cells, scientists can design treatments aimed at preventing cognitive decline.” Don Mahad, a neurologist at the University of Edinburgh who was not involved in the research, agrees, stating that “we can’t ignore these intrinsic vulnerabilities of the nerve cell, and that has to be a treatment target.”

While the research represents an important step forward, Mahad notes that it is “the beginning of a long journey.” The findings provide a foundation for future studies and the development of therapies that could protect the brain’s gray matter and preserve cognitive function in people with MS.

Each year, approximately 10,000 people in the United States are diagnosed with MS. The disease’s unpredictable nature and the lack of effective treatments for its progressive phase underscore the urgency of this new research. By targeting the underlying mechanisms of neuron vulnerability, scientists hope to improve outcomes and quality of life for those living with MS.