Combined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury

Abstract

Spinal cord injury (SCI) causes irreversible tissue damage and severe loss of neurological function. Currently, there are no approved treatments and very few therapeutic targets are under investigation. Here, we combined 4 high-throughput transcriptomics and proteomics datasets, 7 days and 8 weeks following clinically-relevant rat SCI to identify proteins with persistent differential expression post-injury. Out of thousands of differentially regulated entities our combined analysis identified 40 significantly upregulated versus 48 significantly downregulated molecules, which were persistently altered at the mRNA and protein level, 7 days and 8 weeks post-SCI. Bioinformatics analysis was then utilized to identify currently available drugs with activity against the filtered molecules and to isolate proteins with known or unknown function in SCI. Our findings revealed multiple overlooked therapeutic candidates with important bioactivity and established druggability but with unknown expression and function in SCI including the upregulated purine nucleoside phosphorylase (PNP), cathepsins A, H, Z (CTSA, CTSH, CTSZ) and proteasome protease PSMB10, as well as the downregulated ATP citrate lyase (ACLY), malic enzyme (ME1) and sodium-potassium ATPase (ATP1A3), amongst others. This work reveals previously unappreciated therapeutic candidates for SCI and available drugs, thus providing a valuable resource for further studies and potential repurposing of existing therapeutics for SCI.

Integrated Bioinformatics Analysis of Hub Genes and Pathways Associated with a Compression Model of Spinal Cord Injury in Rats

“…Another hub gene, Atp1a3 , was persistently downregulated after SCI. This trend was also observed in a bioinformatics study that combined transcriptome and proteomics of contusive SCI in rats [ 23 ]. Several studies have demonstrated that mutations in Atp1a3 may induce persistent neurological dysfunction [ 24 ].…”

Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

“…On the other hand, CTSs have long been involved in skeletal and bone health and disease [199]. Recently, up-regulation of CTSA, CTSH, and CTSZ has been detected through transcriptomic and proteomic analyses in a rat model of spinal cord injury [200]. In VCP (valosin containing protein) knock out mice, up-regulation of CTSB and CTSD in skeletal muscle correlated with activation of the transcription factor EB [201].…”

Filling the Gaps – A Call for Comprehensive Analysis of Extracellular Matrix of the Glial Scar in Region- and Injury-Specific Contexts

“…Responsible for this are peptidases, include the elastases and matrix metallopeptidases. In spinal cord, another catalytic ECM-associated protein group called cathepsins has recently been highlighted using proteomics and transcriptomics as potential ECM regulators (Tica et al, 2018), providing an example of the multitude of unexplored avenues for ECM and its associated proteins in CNS injury.…”