Neurodegenerative diseases exhibit regional and cell-type-specific patterns in aging and disease 1, but the underlying mechanisms of the potential cell-type-specific neuronal loss remain unclear. Previous studies have shown that in progressive human multiple sclerosis (MS), the cortical layer becomes thinner, and excitatory neurons in layers 2 and 3 of the cortex (L2/3ENs) are selectively vulnerable to degeneration due to the expression of a homologous box similar to CUT 2 (CUX2). This article reports that the burden of L2/3EN DNA damage is higher in MS cortical lesions. The L2/3EN DNA damage and selective loss were reproduced in various demyelinating and pan-cortical inflammatory mouse models, confirming their intrinsic fragility. The functions of Cux2 and activating transcription factor 4 (Atf4) are crucial for the resilience of L2/3ENs in postnatal neuroinflammation, acting on neurons to enhance DNA double-strand break repair. Interferon-γ is a cytokine related to the pathogenesis of MS 3,4, sufficient to elevate reactive oxygen levels, leading to DNA damage-mediated neuronal death and selective depletion of L2/3 neurons in mice. These findings suggest that the DNA damage burden and repair deficiency of CUX2+ L2/3ENs contribute to the selective susceptibility of neuroinflammatory injury. This study was published in Nature under the title "DNA damage burden leads to selective loss of CUX2 neurons in neuroinflammation".
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DOI: 10.1038/s41586-026-10310-3