Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, USA.
Center for Cerebrovascular Research, University of California San Francisco, San Francisco, California, USA.
Clin Transl Med. 2024 Apr;14(4):e1650. doi: 10.1002/ctm2.1650.
Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions.
In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits.
Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function.
ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties.
ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.
尽管已经有许多分子被研究作为脊髓损伤 (SCI) 或缺血性中风的生物标志物，但它们都没有在中枢神经系统 (CNS) 神经元中在低基线表达的情况下被特异性诱导。然而，神经元损伤构成了与 SCI 或中风相关的主要病理学，并与神经学结果密切相关。具有低基线表达和损伤后神经元特异性诱导的生物标志物可能与损伤严重程度和恢复更好地相关，与非神经元标志物或具有组成型表达的泛神经元标志物相比，具有更高的敏感性和特异性。
在动物研究中，年轻成年野生型和全局 Atf3 敲除小鼠接受单侧颈 5 (C5) SCI 或永久性远端大脑中动脉闭塞 (pMCAO)。使用 RNA 测序和 qRT-PCR 评估基因表达，通过免疫染色检测蛋白表达。使用市售的酶联免疫吸附测定 (ELISA) 试剂盒测量动物模型和临床人类样本中的血清 ATF3 水平。
激活转录因子 3 (ATF3) 是周围神经系统中受伤背根神经节感觉神经元的分子标志物，在未受伤的小鼠脊髓或皮质中不表达，但在 SCI 或缺血性中风后分别在脊髓或皮质神经元中特异性诱导。此外，SCI 或缺血性中风后 1 天，小鼠血液中的 ATF3 蛋白水平显著升高。重要的是，在 SCI 或缺血性中风后 24 小时内，临床患者的血清 ATF3 蛋白水平升高。此外，与野生型小鼠相比，Atf3 敲除小鼠在 SCI 或缺血性中风后表现出更差的神经学结果和更大的损伤区域，表明 ATF3 具有神经保护功能。
ATF3 是一种易于测量的、神经元特异性的 SCI 和缺血性中风临床生物标志物，具有神经保护特性。
ATF3 在 SCI 或缺血性中风后分别在脊髓或皮质神经元中特异性诱导，在 SCI 或缺血性中风后 24 小时内，临床患者的血清 ATF3 蛋白水平升高。与野生型小鼠相比，Atf3 敲除小鼠在 SCI 或缺血性中风后表现出更差的神经学结果和更大的损伤区域，表明 ATF3 具有神经保护功能。
