Brain Transcriptome of Autism Spectrum Disorders and Tourette Syndrome Defines Common Targetable Inflammatory Pathways Involving Cytokines, Complement, and Kinase Signalling

BackgroundNeurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, however current management focuses on symptom mitigation, with no approved treatments targeting disease mechanisms. There is accumulating literature implicating the immune system in NDDs, and transcriptomics of post-mortem brain tissue from individuals with NDDs has revealed an inflammatory signal. MethodsWe interrogated two RNA-sequencing datasets of ASD and TS (compared to age-matched controls) and identified the top 1000 differentially expressed genes, to explore commonly enriched pathways using an over-representation analysis through GO, KEGG and Reactome.ResultsIn the ASD analysis, the top 1000 DEGs enriched 754 GO terms (all upregulated), 55 KEGG pathways (54 upregulated), and 109 Reactome pathways (all upregulated), involving inflammation, cytokines, complement, cell signalling and epigenetic regulation. In the TS analysis, the top 1000 DEGs enriched 419 GO terms (416 upregulated), 56 KEGG pathways (all upregulated), and 28 Reactome (all upregulated) pathways, including inflammation, cytokines, signal transduction and immune response to stimuli. Of the top 1000 DEGs from the ASD and TS analyses, 133 DEGs were shared. Interaction networks of the common protein-coding DEGs using STRING revealed 5 central up-regulated hub genes: CSF2RB, HCK, HCLS1, LCP2 and PLEK, which are all kinases involved in cell signalling. Applying KEGG and Reactome analysis to these common DEGs identified pathways involving interleukins, complement activation, and cell signalling pathways. ConclusionsThese findings bring new evidence of shared inflammation in ASD and TS, and provide therapeutic opportunities targeting inflammation, epigenetic machinery, and cell signalling including kinases.