Clinical and Translational Medicine (Apr 2024)
ATF3 is a neuron‐specific biomarker for spinal cord injury and ischaemic stroke
- Jonathan Z. Pan,
- Zhanqiang Wang,
- Wei Sun,
- Peipei Pan,
- Wei Li,
- Yongtao Sun,
- Shoulin Chen,
- Amity Lin,
- Wulin Tan,
- Liangliang He,
- Jacob Greene,
- Virginia Yao,
- Lijun An,
- Rich Liang,
- Qifeng Li,
- Jessica Yu,
- Lingyi Zhang,
- Nikolaos Kyritsis,
- Xuan Duong Fernandez,
- Sara Moncivais,
- Esmeralda Mendoza,
- Pamela Fung,
- Gongming Wang,
- Xinhuan Niu,
- Qihang Du,
- Zhaoyang Xiao,
- Yuwen Chang,
- Peiyuan Lv,
- J. Russell Huie,
- Abel Torres‐Espin,
- Adam R. Ferguson,
- Debra D. Hemmerle,
- Jason F. Talbott,
- Philip R. Weinstein,
- Lisa U. Pascual,
- Vineeta Singh,
- Anthony M. DiGiorgio,
- Rajiv Saigal,
- William D. Whetstone,
- Geoffrey T. Manley,
- Sanjay S. Dhall,
- Jacqueline C. Bresnahan,
- Mervyn Maze,
- Xiangning Jiang,
- Neel S. Singhal,
- Michael S. Beattie,
- Hua Su,
- Zhonghui Guan
Affiliations
- Jonathan Z. Pan
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Zhanqiang Wang
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Wei Sun
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Peipei Pan
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Wei Li
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Yongtao Sun
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Shoulin Chen
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Amity Lin
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Wulin Tan
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Liangliang He
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Jacob Greene
- Medical School University of California San Francisco San Francisco California USA
- Virginia Yao
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Lijun An
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Rich Liang
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Qifeng Li
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Jessica Yu
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Lingyi Zhang
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Nikolaos Kyritsis
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Xuan Duong Fernandez
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Sara Moncivais
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Esmeralda Mendoza
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Pamela Fung
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Gongming Wang
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Xinhuan Niu
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Qihang Du
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Zhaoyang Xiao
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Yuwen Chang
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Peiyuan Lv
- Department of Anesthesiology The Second Affiliated Hospital, Dalian Medical University Dalian China
- J. Russell Huie
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Abel Torres‐Espin
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Adam R. Ferguson
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Debra D. Hemmerle
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Jason F. Talbott
- Department of Radiology University of California San Francisco San Francisco California USA
- Philip R. Weinstein
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Lisa U. Pascual
- Department of Orthopedic Surgery Orthopaedic Trauma Institute University of California San Francisco San Francisco California USA
- Vineeta Singh
- Department of Neurology University of California San Francisco San Francisco California USA
- Anthony M. DiGiorgio
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Rajiv Saigal
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- William D. Whetstone
- Department of Emergency Medicine University of California San Francisco San Francisco California USA
- Geoffrey T. Manley
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Sanjay S. Dhall
- Department of Neurosurgery Harbor UCLA Medical Center Torrance California USA
- Jacqueline C. Bresnahan
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Mervyn Maze
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Xiangning Jiang
- Department of Neurology University of California San Francisco San Francisco California USA
- Neel S. Singhal
- Department of Neurology University of California San Francisco San Francisco California USA
- Michael S. Beattie
- Department of Neurological Surgery University of California San Francisco San Francisco California USA
- Hua Su
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- Zhonghui Guan
- Department of Anesthesia and Perioperative Care University of California San Francisco San Francisco California USA
- DOI
- https://doi.org/10.1002/ctm2.1650
- Journal volume & issue
-
Vol. 14,
no. 4
pp. n/a – n/a
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions ATF3 is an easily measurable, neuron‐specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. Highlights 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.
Keywords
- activating transcription factor 3 (ATF3)
- biomarker
- neuronal injury
- neuroprotection
- spinal cord injury
- stroke
