What does this research mean for the field?

Elevated DNA damage burden and inadequate DNA repair mechanisms, exacerbated by Interferon-γ-induced reactive oxygen species, drive the selective vulnerability and loss of CUX2+ layer 2/3 excitatory neurons in neuroinflammatory conditions such as multiple sclerosis. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

This research aims to understand why certain neurons, specifically CUX2+ excitatory neurons, are more vulnerable during neuroinflammation.

April 3, 2026Nature1 citationsOpen Access

DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

LMLaura MorcomWellcome/MRC Cambridge Stem Cell Institute WXWenlong XiaUniversity of California, San Francisco ZXZhaoyang XuCedars-Sinai Medical Center

Key Points

This research aims to understand why certain neurons, specifically CUX2+ excitatory neurons, are more vulnerable during neuroinflammation.
Examined upper cortical layer thinning in multiple sclerosis (MS) lesions.
Analyzed DNA damage levels in CUX2+ excitatory neurons in MS.
Utilized mouse models to replicate neuroinflammation effects on L2/3 neurons.
Investigated roles of Cux2 and Atf4 in DNA repair and neuron resilience.
L2/3 excitatory neurons showed increased DNA damage in MS lesions.
Increased DNA damage led to selective neuron loss in various demyelination models.
Interferon-γ elevated reactive oxygen species, worsening DNA damage and neuron death.
Cux2 and Atf4 were crucial for repairing DNA damage and maintaining neuron resilience.

Abstract

Abstract Neurodegeneration shows regional and cell-type-specific patterns in ageing and disease 1 , but the underlying mechanisms for cell-type-specific neuronal losses remain poorly understood. Previous studies have shown that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) and that cortical layer 2 and layer 3 (L2/3) excitatory neurons (L2/3ENs) that express CUT-like homeobox 2 ( CUX2 ) are selectively vulnerable to degeneration 2 . Here we report that L2/3ENs within MS cortical lesions have an elevated DNA damage burden. DNA damage and selective loss of L2/3ENs were 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 L2/3ENs during postnatal neuroinflammation, acting in neurons to enhance DNA double-strand break repair. Interferon-γ, a cytokine implicated in MS pathogenesis 3,4 , was sufficient to elevate levels of 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 + L2/3ENs contributes to selective vulnerability in neuroinflammatory injury.

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