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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 that upper cortical layer thinning occurs in progressive human multiple sclerosis (MS) a...

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Main Authors: Morcom, Laura (Author) , Xia, Wenlong (Author) , Xu, Zhaoyang (Author) , Awasthi, Yashika (Author) , Geywitz, Celine (Author) , Ellis, Matthew O. (Author) , Noli, Tomas (Author) , Zulji, Amel (Author) , Yamamoto, Daniel (Author) , Girdler, Gemma C. (Author) , Kai, Li (Author) , Zhu, Keying (Author) , Wei, Mingming (Author) , Tang, Xiao-Yan (Author) , Hoi, Kimberly K. (Author) , Gonzalez-Maya, Julio (Author) , Duncan, Greg J. (Author) , Vaquie, Adrien M. (Author) , Gold Diaz, Diana (Author) , Kawaguchi, Riki (Author) , Liu, Erdong (Author) , Sun, Yu (Author) , Yang, Denny (Author) , Jordan, Gregory D. (Author) , Lu, I.-Ling (Author) , Holmqvist, Staffan (Author) , Bartels, Theresa (Author) , Ridley, Katherine (Author) , Choi, Jennifer Ja-Yoon (Author) , Franco, Santos J. (Author) , Huang, Eric J. (Author) , Emery, Ben (Author) , Geschwind, Daniel (Author) , Schirmer, Lucas (Author) , Balmus, Gabriel (Author) , Popko, Brian (Author) , Fancy, Stephen P. J. (Author) , Rowitch, David H. (Author)
Format: Article (Journal)
Language:English
Published: 01 April 2026
In: Nature
Year: 2026, Pages: 1-10
ISSN:1476-4687
DOI:10.1038/s41586-026-10310-3
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41586-026-10310-3
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41586-026-10310-3
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Author Notes:Laura Morcom, Wenlong Xia, Zhaoyang Xu, Yashika Awasthi, Celine Geywitz, Matthew O. Ellis, Tomas Noli, Amel Zulji, Daniel Yamamoto, Gemma C. Girdler, Li Kai, Keying Zhu, Mingming Wei, Xiao-Yan Tang, Kimberly K. Hoi, Julio Gonzalez-Maya, Greg J. Duncan, Adrien M. Vaquie, Diana Gold Diaz, Riki Kawaguchi, Erdong Liu, Yu Sun, Denny Yang, Gregory D. Jordan, I.-Ling Lu, Staffan Holmqvist, Theresa Bartels, Katherine Ridley, Jennifer Ja-Yoon Choi, Santos J. Franco, Eric J. Huang, Ben Emery, Daniel Geschwind, Lucas Schirmer, Gabriel Balmus, Brian Popko, Stephen P.J. Fancy & David H. Rowitch
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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.
Item Description:Gesehen am 14.04.2026
Physical Description:Online Resource
ISSN:1476-4687
DOI:10.1038/s41586-026-10310-3

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