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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".
Reference News:
DOI: 10.1038/s41586-026-10310-3
