DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

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

doi:10.1038/s41586-026-10310-3

DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

Nature. 2026 May;653(8115):809-818. doi: 10.1038/s41586-026-10310-3. Epub 2026 Apr 1.

Authors

Laura Morcom^#^{1

2

3

4}, Wenlong Xia^#⁵, Zhaoyang Xu^{1

3

6

7}, Yashika Awasthi⁸, Celine Geywitz⁹, Matthew O Ellis^{2

4}, Tomas Noli⁹, Amel Zulji⁹, Daniel Yamamoto^{1

3}, Gemma C Girdler^{1

3}, Li Kai⁸, Keying Zhu⁵, Mingming Wei⁵, Xiao-Yan Tang⁵, Kimberly K Hoi⁵, Julio Gonzalez-Maya⁵, Greg J Duncan¹⁰, Adrien M Vaquie^{1

3}, Diana Gold Diaz^{1

3}, Riki Kawaguchi^{11

12}, Erdong Liu⁸, Yu Sun^{2

4}, Denny Yang^{2

4}, Gregory D Jordan^{1

3}, I-Ling Lu^{13

14}, Staffan Holmqvist^{1

3}, Theresa Bartels^{1

3}, Katherine Ridley^{1

3}, Jennifer Ja-Yoon Choi¹⁵, Santos J Franco¹⁶, Eric J Huang¹⁵, Ben Emery¹⁷, Daniel Geschwind^{12

18

19}, Lucas Schirmer^{9

20

21}, Gabriel Balmus^{2

4

22}, Brian Popko⁸, Stephen P J Fancy²³, David H Rowitch^{24

25

26

27

28

29}

Affiliations

¹ Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
² UK Dementia Research Institute at the University of Cambridge, University of Cambridge, Cambridge, UK.
³ Department of Paediatrics, University of Cambridge, Cambridge, UK.
⁴ Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁵ Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
⁷ Department of Neurosurgery, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA.
⁸ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁹ Division of Neuroimmunology, Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
¹⁰ Department of Neurology, Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, OR, USA.
¹¹ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹² Department of Neurology, University of California Los Angeles, Los Angeles, CA, USA.
¹³ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA.
¹⁴ Department of Pediatrics, Division of Neonatology, University of California San Francisco, San Francisco, CA, USA.
¹⁵ Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
¹⁶ Department of Pediatrics, Section of Developmental Biology, University of Colorado-Anschutz Medical Campus, Denver, CO, USA.
¹⁷ Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, OR, USA.
¹⁸ Program in Neurogenetics, Departments of Neurology and Human Genetics, Institute of Precision Health, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
¹⁹ Center for Autism Research and Treatment, Department of Psychiatry and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
²⁰ Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany.
²¹ Center for Translational Neuroscience and Institute for Innate Immunoscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
²² Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania.
²³ Division of Neuroimmunology and Glial Biology, Department of Neurology, University of California San Francisco, San Francisco, CA, USA. stephen.fancy@ucsf.edu.
²⁴ Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. david.rowitch@csmc.edu.
²⁵ Department of Paediatrics, University of Cambridge, Cambridge, UK. david.rowitch@csmc.edu.
²⁶ Department of Pediatrics, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA. david.rowitch@csmc.edu.
²⁷ Department of Neurosurgery, Cedars-Sinai Guerin Children's, Los Angeles, CA, USA. david.rowitch@csmc.edu.
²⁸ The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA, USA. david.rowitch@csmc.edu.
²⁹ Department of Pediatrics, Division of Neonatology, University of California San Francisco, San Francisco, CA, USA. david.rowitch@csmc.edu.

^# Contributed equally.

Abstract

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 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.

MeSH terms

Animals
Cell Death
DNA Breaks, Double-Stranded
DNA Damage*
DNA Repair
Disease Models, Animal
Female
Homeodomain Proteins* / genetics
Homeodomain Proteins* / metabolism
Humans
Interferon-gamma / metabolism
Male
Mice
Multiple Sclerosis / genetics
Multiple Sclerosis / pathology
Neuroinflammatory Diseases* / genetics
Neuroinflammatory Diseases* / pathology
Neurons* / metabolism
Neurons* / pathology
Reactive Oxygen Species / metabolism

Substances

Homeodomain Proteins
Interferon-gamma
Reactive Oxygen Species