DNA damage burden causes selective CUX2 neuron loss in neuroinflammation
Summary
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 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 degeneration2. 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 pathogenesis3,4, 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. © 2026. The Author(s).
| Authors | Morcom L, Xia W, Xu Z, Awasthi Y, Geywitz C, Ellis MO, Noli T, Zulji A, Yamamoto D, Girdler GC, Kai L, Zhu K, Wei M, Tang XY, Hoi KK, Gonzalez-Maya J, Duncan GJ, Vaquie AM, Gold Diaz D, Kawaguchi R, Liu E, Sun Y, Yang D, Jordan GD, Lu IL, Holmqvist S, Bartels T, Ridley K, Choi JJ, Franco SJ, Huang EJ, Emery B, Geschwind D, Schirmer L, Balmus G, Popko B, Fancy SPJ, Rowitch DH |
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| Journal | Nature |
| Publication Date | 2026 May;653(8115):809-818 |
| PubMed | 41922773 |
| PubMed Central | PMC13190333 |
| DOI | 10.1038/s41586-026-10310-3 |