DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

Abstract

Neurodegeneration shows regional and cell-type-specific patterns in ageing and 69 disease1, but the underlying mechanisms for cell type-specific neuronal losses remain 70 poorly understood. Previous studies have shown upper cortical layer thinning in 71 progressive human multiple sclerosis (MS) and that cortical layer 2/3 excitatory 72 neurons (L2/3ENs) that express CUT-like homeobox 2 (Cux2) are selectively 73 vulnerable to degeneration2. Here, we report that L2/3ENs within MS cortical lesions 74 have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs 75 was recapitulated in diverse mouse models of demyelination and pan-cortical 76 inflammation, confirming their intrinsic vulnerability. Functions of Cux2 and 77 Activating transcription factor 4 (Atf4) were essential for resilience of L2/3ENs during 78 postnatal neuroinflammation, acting in neurons to enhance DNA double-strand 79 repair. Interferon-γ, a cytokine implicated in MS pathogenesis3,4, was sufficient to 80 elevate reactive oxygen species leading to DNA damage-mediated neuronal death in 81 vitro and caused selective depletion of L2/3 neurons in mice. These findings indicate 82 that DNA damage burden and inadequate repair in CUX2+ L2/3ENs contributes to 83 selective vulnerability in neuroinflammatory injury.