DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease1, but the underlying mechanisms for cell type-specific neuronal losses remain poorly understood. Previous studies have shown upper cortical layer thinning in progressive human multiple sclerosis (MS) and that cortical layer 2/3 excitatory neurons (L2/3 ENs) that express CUT like homeobox 2 (CUX2) are selectively vulnerable to degeneration2. Here, we report that L2/3 ENs within MS cortical lesions have elevated DNA damage. DNA damage and selective loss of L2/3 ENs was recapitulated in diverse mouse models of demyelination and pan-cortical inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and Activating transcription factor 4 (Atf4) were essential for resilience of L2/3 ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to elevate reactive oxygen species leading to DNA damage-mediated neuronal death in vitro and caused selective depletion of L2/3 neurons in mice. These findings indicate that DNA damage burden and inadequate repair in CUX2+ L2/3 ENs contributes to selective vulnerability in neuroinflammatory injury.