剑桥大学David H. Rowitch小组近日取得一项新成果。经过不懈努力，他们探明了神经炎症中DNA损伤负荷导致选择性CUX2神经元丢失。该项研究成果发表在2026年4月1日出版的《自然》上。

在这里，研究人员报告多发性硬化症皮质病变内的L2/3ENs具有升高的DNA损伤负担。在多种脱髓鞘和泛皮质炎症模型中重现了L2/3ENs的DNA损伤和选择性丢失，证实了它们内在的脆弱性。Cux2和激活转录因子4（Atf4）的功能对L2/3ENs在出生后神经炎症中的恢复能力至关重要，它们在神经元中起作用，增强DNA双链断裂修复。干扰素-γ是一种与MS发病机制有关的细胞因子，它足以提高活性氧水平，导致体外DNA损伤介导的神经元死亡，并在小鼠中引起L2/3神经元的选择性耗竭。这些发现表明，CUX2⁺ L2/3ENs的DNA损伤负担和修复不足有助于神经炎症损伤的选择性易感性。

据了解，神经退行性变在衰老和疾病中显示出区域和细胞类型特异性模式，但细胞类型特异性神经元损失的潜在机制仍然知之甚少。先前的研究表明，进行性多发性硬化症（MS）发生皮质上层变薄，表达CUX2的皮质第2层和第3层（L2/3）兴奋性神经元（L2/3ENs）选择性地易发生变性2。

附：英文原文

Title: DNA damage burden causes selective CUX2 neuron loss in neuroinflammation

Author: Morcom, Laura, Xia, Wenlong, Xu, Zhaoyang, Awasthi, Yashika, Geywitz, Celine, Ellis, Matthew O., Noli, Tomas, Zulji, Amel, Yamamoto, Daniel, Girdler, Gemma C., Kai, Li, Zhu, Keying, Wei, Mingming, Tang, Xiao-Yan, Hoi, Kimberly K., Gonzalez-Maya, Julio, Duncan, Greg J., Vaquie, Adrien M., Gold Diaz, Diana, Kawaguchi, Riki, Liu, Erdong, Sun, Yu, Yang, Denny, Jordan, Gregory D., Lu, I-Ling, Holmqvist, Staffan, Bartels, Theresa, Ridley, Katherine, Choi, Jennifer Ja-Yoon, Franco, Santos J., Huang, Eric J., Emery, Ben, Geschwind, Daniel, Schirmer, Lucas, Balmus, Gabriel, Popko, Brian, Fancy, Stephen P. J., Rowitch, David H.

Issue&Volume: 2026-04-01

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 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.

DOI: 10.1038/s41586-026-10310-3

Source: https://www.nature.com/articles/s41586-026-10310-3