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Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy
Qianqian Ge, … , Li Shen, Jiadong Chen
Qianqian Ge, … , Li Shen, Jiadong Chen
Published March 3, 2025
Citation Information: J Clin Invest. 2025;135(5):e188942. https://doi.org/10.1172/JCI188942.
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Research Article Aging Neuroscience Article has an altmetric score of 9

Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy

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Abstract

The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.

Authors

Qianqian Ge, Jiachao Yang, Fei Huang, Xinyue Dai, Chao Chen, Jingxin Guo, Mi Wang, Mengyue Zhu, Yijie Shao, Yuxian Xia, Yu Zhou, Jieqiao Peng, Suixin Deng, Jiachen Shi, Yiqi Hu, Huiying Zhang, Yi Wang, Xiaoqun Wang, Xiao-Ming Li, Zhong Chen, Yousheng Shu, Jun-Ming Zhu, Jianmin Zhang, Ying Shen, Shumin Duan, Shengjin Xu, Li Shen, Jiadong Chen

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Figure 5

Expression of senescent cell markers in histopathological neurons in people with drug-resistant epilepsy.

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Expression of senescent cell markers in histopathological neurons in peo...
(A–C) Representative images (A) and statistical quantification (C) of SA-β-Gal staining showed that β-Gal–positive cells were present in the epileptic focus of FCD (n = 35 samples), TLE (n = 17 samples), and PT (n = 11 samples), but not in control cortical tissues with no history of epilepsy (n = 4 samples). Scale bars: 200 μm (A), 20 μm in zoom-in images (B) of box area in A. Data are presented as mean ± SEM. Kruskal-Wallis test with Dunn’s multiple comparisons test. **P < 0.01, *P < 0.05. (D–G) Representative images (D) and statistical quantification (F) showing the expression of marker genes in SMI-positive dysmorphic neurons compared with in SMI-negative neurons in focal cortical dysplasia or control brain samples (E and G). Arrows indicate coexpression of senescent cell markers with SMI and NeuN. Arrowheads indicated no Lamin B1 expression were detected in SMI-positive histopathological dysmorphic neurons. Data are presented as cell numbers quantified from 5 individual samples for each marker (F; Fisher’s exact test. ****P < 0.0001). Data are presented as mean ± SEM (G; 2-tailed Mann-Whitney test). Scale bar, 50 μm; 10 μm for zoom-in images.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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