ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Activating Transcription Factor 3*/metabolism ; Activating Transcription Factor 3*/genetics ; Biomarkers*/metabolism ; Biomarkers*/blood ; Ischemic Stroke*/metabolism ; Ischemic Stroke*/genetics ; Ischemic Stroke*/blood ; Neurons*/metabolism ; Spinal Cord Injuries*/metabolism ; Spinal Cord Injuries*/genetics ; Spinal Cord Injuries*/complications; Animals ; Female ; Humans ; Male ; Mice ; Disease Models, Animal ; Mice, Knockout

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.
(© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Eur Cardiol. 2020 Jul 15;15:e56. (PMID: 32742310)
Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1622-7. (PMID: 24474789)
Science. 2000 Feb 25;287(5457):1500-3. (PMID: 10688801)
ILAR J. 2007;48(4):385-95. (PMID: 17712224)
Neuron. 2020 Oct 14;108(1):128-144.e9. (PMID: 32810432)
Mol Cell Biol. 2004 Jul;24(13):5721-32. (PMID: 15199129)
Nat Commun. 2019 Apr 3;10(1):1523. (PMID: 30944313)
Brain Behav. 2022 Apr;12(4):e2522. (PMID: 35263513)
Lung Cancer. 2012 May;76(2):138-43. (PMID: 22153832)
Curr Mol Med. 2008 May;8(3):173-86. (PMID: 18473818)
Eur J Intern Med. 2016 Apr;29:9-21. (PMID: 26723523)
Expert Rev Mol Diagn. 2018 Feb;18(2):165-180. (PMID: 29338452)
PLoS One. 2013 Aug 09;8(8):e72567. (PMID: 23951329)
Stroke. 2013 Jan;44(1):190-7. (PMID: 23168453)
World Neurosurg. 2015 May;83(5):867-78. (PMID: 23524031)
Exp Neurol. 2020 Jun;328:113273. (PMID: 32142803)
Aging Dis. 2019 Feb 01;10(1):12-22. (PMID: 30705764)
Lancet Neurol. 2009 Apr;8(4):355-69. (PMID: 19233729)
J Neurotrauma. 2020 Dec 1;37(23):2460-2467. (PMID: 32854584)
Mol Cell Neurosci. 2006 May-Jun;32(1-2):143-54. (PMID: 16713293)
J Neurosci. 2007 Jul 25;27(30):7911-20. (PMID: 17652582)
J Neurotrauma. 2018 Oct 1;35(19):2317-2329. (PMID: 29463176)
Toxicol Pathol. 2006;34(1):91-3. (PMID: 16507549)
Mol Cell Neurosci. 2000 Feb;15(2):170-82. (PMID: 10673325)
Brain Res. 1997 Mar 14;751(1):37-46. (PMID: 9098566)
Stroke. 2007 Feb;38(2 Suppl):652-60. (PMID: 17261709)
Br J Anaesth. 2019 Dec;123(6):827-838. (PMID: 31623841)
Cell Tissue Res. 2019 Aug;377(2):125-151. (PMID: 31065801)
J Neurosci. 2002 Feb 15;22(4):1303-15. (PMID: 11850458)
PLoS One. 2016 Apr 18;11(4):e0153835. (PMID: 27089041)
Front Neurol. 2021 Feb 05;12:619721. (PMID: 33633673)
Gene Expr. 1999;7(4-6):321-35. (PMID: 10440233)
Neuroscience. 2012 Sep 18;220:100-8. (PMID: 22704967)
J Neurotrauma. 2006 Jan;23(1):36-54. (PMID: 16430371)
J Exp Med. 2021 Mar 1;218(3):. (PMID: 33512429)
Neural Regen Res. 2019 Sep;14(9):1583-1593. (PMID: 31089057)
Neural Regen Res. 2019 Jul;14(7):1262-1270. (PMID: 30804258)
Clin Transl Med. 2024 Apr;14(4):e1650. (PMID: 38649772)
Biochem Biophys Res Commun. 2017 Jul 1;488(3):522-527. (PMID: 28522294)
Prog Brain Res. 2002;137:37-47. (PMID: 12440358)
JAMA. 2014 Mar 19;311(11):1143-9. (PMID: 24643604)
PLoS One. 2014 Jul 14;9(7):e102027. (PMID: 25019623)
ASN Neuro. 2018 Jan-Dec;10:1759091418784357. (PMID: 29950099)
Mol Neurobiol. 2018 Aug;55(8):6436-6448. (PMID: 29307082)
Spinal Cord. 2019 Oct;57(10):819-831. (PMID: 31273298)
Elife. 2021 Nov 16;10:. (PMID: 34783309)
Eur J Neurosci. 2007 Jan;25(2):362-72. (PMID: 17284176)
J Neurosci Methods. 2002 Jun 30;117(2):207-14. (PMID: 12100987)
BMC Genomics. 2017 Feb 15;18(1):173. (PMID: 28201982)
Stat Med. 1990 Jul;9(7):811-8. (PMID: 2218183)
Lancet Neurol. 2018 Sep;17(9):782-789. (PMID: 30054151)
Cell Death Differ. 2007 Jan;14(1):32-43. (PMID: 17082813)
Front Neurol. 2014 Jul 07;5:116. (PMID: 25071704)
Clin Chem. 2009 Nov;55(11):1977-83. (PMID: 19745058)
J Neurotrauma. 2003 Nov;20(11):1223-31. (PMID: 14651809)
J Cereb Blood Flow Metab. 2021 Sep;41(9):2162-2173. (PMID: 33641516)
J Neurochem. 2014 Nov;131(4):498-508. (PMID: 25040630)
Nat Med. 2019 Jun;25(6):898-908. (PMID: 31160817)
Neurosci Res. 2011 Aug;70(4):428-34. (PMID: 21616101)
Brain Res. 2005 Feb 21;1035(1):24-31. (PMID: 15713273)
Stroke. 2014 Jul;45(7):2101-6. (PMID: 24876084)
Front Mol Neurosci. 2012 Feb 14;5:7. (PMID: 22347845)
Neuroscience. 2020 Jan 15;425:146-156. (PMID: 31785351)
Genes Dev. 1989 Dec;3(12B):2083-90. (PMID: 2516827)
Exp Neurol. 2007 Feb;203(2):555-67. (PMID: 17067578)
Physiol Rev. 2018 Apr 1;98(2):813-880. (PMID: 29488822)
Neurotherapeutics. 2010 Jan;7(1):3-12. (PMID: 20129492)
J Clin Pathol. 1978 Jun;31(6):507-20. (PMID: 78929)
Front Mol Neurosci. 2023 Jan 18;15:1079338. (PMID: 36743288)
J Neurosci Res. 2016 May;94(5):378-88. (PMID: 26900013)

R01 NS100801 United States NS NINDS NIH HHS; R01NS100801 United States NS NINDS NIH HHS

Keywords: activating transcription factor 3 (ATF3); biomarker; neuronal injury; neuroprotection; spinal cord injury; stroke

0 (Activating Transcription Factor 3)
0 (ATF3 protein, human)
0 (Atf3 protein, mouse)
0 (Biomarkers)

Date Created: 20240422 Date Completed: 20240429 Latest Revision: 20240503

20240504

PMC11035380

10.1002/ctm2.1650

38649772