Two new studies published in Nature have identified a mechanism behind the selective death of specific cortical neurons in progressive multiple sclerosis (MS), pointing to DNA damage accumulation as a primary driver of neurodegeneration in the condition’s later stages.


Researchers focused on a population of neurons in the human cortex known as CUX2 neurons, previously identified as particularly susceptible to degeneration in progressive MS. These cells occupy two layers of the cortex associated with higher cognitive functions, including reasoning and computation. Because CUX2 neurons divide rapidly during brain development, they carry an elevated risk of accruing DNA damage from an early stage.


The first study identified a DNA repair mechanism that CUX2 neurons depend on for survival during development. A protein called ATF4 initiates the DNA repair response in these cells. When ATF4 was disabled in mice, CUX2 neurons died rapidly, confirming the protein’s role in maintaining cellular integrity.


The second study demonstrated that DNA damage is the principal cause of CUX2 cell loss in MS. Brain tissue from people with MS showed significantly higher levels of DNA damage in the cortical layers where CUX2 neurons reside compared with tissue from healthy individuals. Mice engineered to develop an MS-like condition similarly showed CUX2 cell death attributable to DNA damage rather than direct immune attack.


The researchers propose that early developmental DNA damage leaves CUX2 neurons with reduced capacity to withstand the additional cellular stress imposed by MS-related inflammation later in life. Current MS treatments focus primarily on reducing immune-mediated inflammation or restoring myelin to nerve fibres. The authors suggest that targeting the intrinsic vulnerabilities of these neurons represents a new and largely unexplored therapeutic direction for addressing cognitive decline in progressive MS.


Sources: Xia W et al. Expansion of outer cortical CUX2 neurons requires adaptations for DNA repair. Nature (2026). DOI: 10.1038/s41586-026-10290-4. Morcom L et al. DNA damage burden causes selective CUX2 neuron loss in neuroinflammation. Nature (2026). DOI: 10.1038/s41586-026-10290-4