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乳腺癌易感蛋白 1（BRCA1）通过 NRF2 介导的抗氧化途径拯救脑缺血/再灌注损伤中的神经元。

Breast cancer susceptibility protein 1 (BRCA1) rescues neurons from cerebral ischemia/reperfusion injury through NRF2-mediated antioxidant pathway.

机构信息

Department of Neurology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China.

Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada; Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui 241001, China.

出版信息

Redox Biol. 2018 Sep;18:158-172. doi: 10.1016/j.redox.2018.06.012. Epub 2018 Jul 7.

DOI:10.1016/j.redox.2018.06.012
PMID:30014904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6068089/
Abstract

Cellular oxidative stress plays a vital role in the pathological process of neural damage in cerebral ischemia/reperfusion (I/R). The breast cancer susceptibility protein 1 (BRCA1), a tumor suppressor, can modulate cellular antioxidant response and DNA repair. Yet the role of BRCA1 in cerebral I/R injury has not been explored. In this study, we observed that BRCA1 was mainly expressed in neurons and was up-regulated in response to I/R insult. Overexpression of BRCA1 attenuated reactive oxygen species production and lipid peroxidation. Enhanced BRCA1 expression promoted DNA double strand break repair through non-homologous end joining pathway. These effects consequently led to neuronal cell survival and neurological recovery. Mechanically, BRCA1 can interact with the nuclear factor (erythroid-derived 2)-like 2 (NRF2) through BRCA1 C-terminal (BRCT) domain. The cross-talk between BRCT and NRF2 activated the NRF2/Antioxidant Response Element signaling pathway and thus protected injured neurons during cerebral I/R. In conclusion, enhanced BRCA1 after cerebral I/R injury may attenuate or prevent neural damage from I/R via NRF2-mediated antioxidant pathway. The finding may provide a potential therapeutic target against ischemic stroke.

摘要

细胞氧化应激在脑缺血/再灌注（I/R）引起的神经损伤的病理过程中起着至关重要的作用。乳腺癌易感蛋白 1（BRCA1）是一种肿瘤抑制因子，可调节细胞抗氧化反应和 DNA 修复。然而，BRCA1 在脑 I/R 损伤中的作用尚未被探索。在这项研究中，我们观察到 BRCA1 主要表达于神经元，并在 I/R 损伤后上调。BRCA1 的过表达可减轻活性氧（ROS）的产生和脂质过氧化。增强的 BRCA1 表达通过非同源末端连接途径促进 DNA 双链断裂修复。这些作用最终导致神经元细胞存活和神经功能恢复。在机制上，BRCA1 可以通过 BRCA1 C 端（BRCT）结构域与核因子（红细胞衍生 2）样 2（NRF2）相互作用。BRCT 与 NRF2 之间的串扰激活了 NRF2/抗氧化反应元件信号通路，从而在脑 I/R 期间保护受损神经元。总之，脑 I/R 损伤后 BRCA1 的增强可能通过 NRF2 介导的抗氧化途径减轻或预防 I/R 引起的神经损伤。这一发现可能为缺血性中风提供一个潜在的治疗靶点。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1362/6068089/293d2954ec91/gr8.jpg
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