ATF3 is a neuron‐specific biomarker for spinal cord injury and ischaemic stroke
Authors: Pan Jonathan Z. , Wang Zhanqiang , Sun Wei , Pan Peipei , Li Wei , Sun Yongtao , Chen Shoulin , Lin Amity , Tan Wulin , He Liangliang , Greene Jacob , Yao Virginia , An Lijun , Liang Rich , Li Qifeng , Yu Jessica , Zhang Lingyi , Kyritsis Nikolaos , Fernandez Xuan Duong , Moncivais Sara , Mendoza Esmeralda , Fung Pamela , Wang Gongming , Niu Xinhuan , Du Qihang , Xiao Zhaoyang , Chang Yuwen , Lv Peiyuan , Huie J. Russell , Torres‐Espin Abel , Ferguson Adam R. , Hemmerle Debra D. , Talbott Jason F. , Weinstein Philip R. , Pascual Lisa U. , Singh Vineeta , DiGiorgio Anthony M. , Saigal Rajiv , Whetstone William D. , Manley Geoffrey T. , Dhall Sanjay S. , Bresnahan Jacqueline C. , Maze Mervyn , Jiang Xiangning , Singhal Neel S. , Beattie Michael S. , Su Hua , Guan Zhonghui 
Published: April 2024

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.