Image_5_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.PDF

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Image_2_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.PDF

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Table_4_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.XLSX

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Table_2_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.XLSX

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Image_4_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.PDF

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Image_1_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.PDF

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Table_1_Common targetable inflammatory pathways in brain transcriptome of autism spectrum disorders and Tourette syndrome.DOCX

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR) <0.05] in the ASD dataset (n = 248) and the TS dataset (n = 156) enriched pathways involving inflammation, cytokines, signal transduction and cell signalling. Of the DEGs from the ASD and TS analyses, 23 were shared, all of which were up-regulated: interaction networks of the common protein-coding genes using STRING revealed 5 central up-regulated hub genes: CCL2, ICAM1, HMOX1, MYC, and SOCS3. Applying KEGG and Reactome analysis to the 23 common genes identified pathways involving the innate immune response such as interleukin and interferon signalling pathways. These findings bring new evidence of shared immune signalling in ASD and TS brain transcriptome, to support the overlapping symptoms that individuals with these complex disorders experience.</p

Clinical phenotypes associated with <i>GARS</i> variants in human.

<p>Clinical phenotypes associated with <i>GARS</i> variants in human.</p

Compound heterozygous mutations in glycyl-tRNA synthetase (<i>GARS</i>) cause mitochondrial respiratory chain dysfunction - Fig 1

<p><b>A</b>) Sanger sequencing profile of <i>GARS</i> from the proband and parents showing c.803C>T; p.(Thr268Ile) variant is heterozygous in the proband and the father. <b>B)</b> Sanger sequencing profile of <i>GARS</i> from the proband and parents showing c.1234C>T; p.(Arg412Cys) variant is heterozygous in the proband and the mother. <b>C)</b> Evolutionary sequence conservations of the altered amino acid residues p.Thr268 and p. Arg412 are denoted in bold red in boxes.</p

Spectrophotometric MRC enzyme diagnostic data in skeletal muscle, liver and fibroblasts.

<p>Patient liver and muscle samples. Data are expressed as activity relative to protein and as % CS ratio, which represents % of the normal control mean value when expressed relative to Citrate Synthase. Bold characters indicate clinically significant abnormal values (H–high, L–low). Complex I (CI), NADH-coenzyme Q1 oxidoreductase; Complex II (CII), succinate-coenzyme Q1 oxidoreductase; Complex III (CIII), decylbenzylquinol-cytochrome c oxidoreductase; Complex IV, cytochrome c oxidase (CIV).</p