Ting Ma, Yumeng Li, Pengyu Ren, Shiquan Wang, Xianglong Liu, Wenbo Lv, Wugang Hou, Wenqiang Zuo, Weiqiang Lin, Jian Sima, Anqi Geng. 2024. DNA2 knockout aggravates cerebral ischemia/reperfusion injury by reducing postsynaptic Homer1a. Zoological Research. DOI: 10.24272/j.issn.2095-8137.2024.269
Citation: Ting Ma, Yumeng Li, Pengyu Ren, Shiquan Wang, Xianglong Liu, Wenbo Lv, Wugang Hou, Wenqiang Zuo, Weiqiang Lin, Jian Sima, Anqi Geng. 2024. DNA2 knockout aggravates cerebral ischemia/reperfusion injury by reducing postsynaptic Homer1a. Zoological Research. DOI: 10.24272/j.issn.2095-8137.2024.269

DNA2 knockout aggravates cerebral ischemia/reperfusion injury by reducing postsynaptic Homer1a

  • DNA2, a multifunctional enzyme encompassing structure-specific nuclease, 5′-to-3′ helicase, and DNA-dependent ATPase activities, is pivotal in the cellular response to DNA damage. However, its involvement in cerebral ischemia/reperfusion (IR) injury remains elusive. In this study, we utilized DNA2 conditional knockout (cKO) mice (Nestin-Cre) to induce middle cerebral artery occlusion (MCAO) as an animal model of cerebral IR. Our results demonstrate a gradual upregulation of DNA2 expression, peaking at 72 hours post-MCAO. Notably, cKO mice exhibited more pronounced brain damage, neurological deficits, and neuronal apoptosis in the penumbra following MCAO. Additionally, DNA2 expression was elevated in an oxygen-glucose deprivation/reoxygenation (OGD/R) cell culture model, where DNA2 knockdown (KD) exacerbated neuronal apoptosis and oxidative stress. To further dissect the mechanisms underlying DNA2-mediated regulation of cerebral IR injury, we conducted whole transcriptome sequencing (RNA-seq) on ischemic penumbra tissues. Our data unveiled a significant downregulation of Homer1 in cKO mice. Moreover, in cell cultures, overexpression of Homer1a ameliorated DNA2 KD-induced neuronal apoptosis. Collectively, our findings demonstrate that DNA2 deficiency exacerbates cerebral IR injury by downregulating Homer1a.
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