The MAPK Signaling Pathway Presents Novel Molecular Targets for Therapeutic Intervention after Traumatic Spinal Cord Injury: A Comparative Cross-Species Transcriptional Analysis

Abstract

Despite the debilitating consequences following traumatic spinal cord injury (SCI), there is a lack of safe and effective therapeutics in the clinic. The species-specific responses to SCI present major challenges and opportunities for the clinical translation of biomolecular and pharmacological interventions. Recent transcriptional analyses in preclinical SCI studies have provided a snapshot of the local SCI-induced molecular responses in different animal models. However, the variation in the pathogenesis of traumatic SCI across species is yet to be explored. This study aims to identify and characterize the common and inconsistent SCI-induced differentially expressed genes across species to identify potential therapeutic targets of translational relevance. A comprehensive search of open-source transcriptome datasets identified four cross-compatible microarray experiments in rats, mice, and salamanders. We observed consistent expressional changes in extracellular matrix components across the species. Conversely, salamanders showed downregulation of intracellular MAPK signaling compared to rodents. Additionally, sequence conservation and interactome analyses highlighted the well-preserved sequences of Fn1 and Jun with extensive protein-protein interaction networks. Lastly, in vivo immunohistochemical staining for fibronectin was used to validate the observed expressional pattern. These transcriptional changes in extracellular and MAPK pathways present potential therapeutic targets for traumatic SCI with promising translational relevance.

Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair

“…Ligand-receptor interactions involve WNT7A-FZD2/6/LRP5 and PDGFA-PDGFRB, whereby Glia/ERG- and OPC-derived WNT7A and PDGFA are received by FZD2/6/LRP5- and PDGFRB-expressing neurons. Highlighting the requirement for extracellular matrix (ECM) remodeling and signaling to enact a pro-regenerative response (Bradbury et al, 2002; Monaghan et al, 2007; Zavvarian et al, 2021), multiple cell types including Neurons A express Fibronectin 1 (FN1), which is predicted to direct strong interactions with SDC4-, ITGAV-, ITGA5- and ITGB1-expressing cells. Conversely, Glia/ERGs are a major source of outgoing SEMA6A signaling, received by PLXNA4-expressing neurons to regulate axon guidance (Carulli et al, 2021; Runker et al, 2008; Squair et al ., 2023; Syed et al, 2016; Yoshida, 2012).…”

Identification of hub genes and key pathways in spinal cord injury via bioinformatics analysis

“…The enhancement of the neuroplasticity and tissue repair following SCI are key to the functional recovery of SCI patients (18). However, the effects of current treatment for SCI are still limited in neural regeneration, and understanding the underlying mechanisms in the process of SCI provides opportunities for the targeted therapy of SCI (19,20). In this study, we identified 6 hub genes (Cd44, Timp1, Loxl1, Col6a1, Col3a1, Col5a1) and key biological mechanisms involved in the process of SCI based on bioinformatics analysis.…”

Translational Relevance of Secondary Intracellular Signaling Cascades Following Traumatic Spinal Cord Injury

“…The current clinically approved neuroprotective regimen, involving the administration of methylprednisolone sodium succinate (MPSS), is known to suppress the immune response through alteration of the MAPK network [ 65 , 66 , 67 , 68 ]. Interestingly, a recent comparative cross-species transcriptional analysis has highlighted the therapeutic potential of MAPK signaling in traumatic SCI [ 22 ]. The scarless healing process post-SCI seen in regenerative species, such as salamanders, may be explained by the downregulation of MAPK orthologs.…”

“…The scarless healing process post-SCI seen in regenerative species, such as salamanders, may be explained by the downregulation of MAPK orthologs. Due to the observation that these genes are upregulated in mammals and downregulated in salamanders post-SCI, they may be worth investigating as potential therapeutic targets [ 22 ].…”

“…Although the clinical manifestation of these pathologies is heterogeneous, they often result in sensory loss and flaccid paralysis due to the loss of peripheral innervation at and distal to the injury site, in addition to autonomic disturbances, such as neurogenic shock and autonomic dysreflexia [ 19 , 20 , 21 ]. Damage to spinal interneurons, such as in central cord syndrome, can also result in pain, spasticity, or functional inactivation [ 22 ].…”