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Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment

BACKGROUND: Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD. PURPOSE: To delineate...

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Autores principales: Gevezova, Maria, Sbirkov, Yordan, Sarafian, Victoria, Plaimas, Kitiporn, Suratanee, Apichat, Maes, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10275703/
https://www.ncbi.nlm.nih.gov/pubmed/37334258
http://dx.doi.org/10.1016/j.bbih.2023.100646
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author Gevezova, Maria
Sbirkov, Yordan
Sarafian, Victoria
Plaimas, Kitiporn
Suratanee, Apichat
Maes, Michael
author_facet Gevezova, Maria
Sbirkov, Yordan
Sarafian, Victoria
Plaimas, Kitiporn
Suratanee, Apichat
Maes, Michael
author_sort Gevezova, Maria
collection PubMed
description BACKGROUND: Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD. PURPOSE: To delineate these underpinning signatures, we examined the two largest gene expression meta-analysis datasets obtained from the brain and peripheral blood mononuclear cells (PBMCs) of 1355 ASD patients and 1110 controls. METHODS: We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients. RESULTS: Transcription factor network analyses in up- and down-regulated genes in brain tissue and PBMCs in ASD showed eight main transcription factors, namely: BCL3, CEBPB, IRF1, IRF8, KAT2A, NELFE, RELA, and TRIM28. The upregulated gene networks in PBMCs of ASD patients are strongly associated with activated immune-inflammatory pathways, including interferon-α signaling, and cellular responses to DNA repair. Enrichment analyses of the upregulated CNS gene networks indicate involvement of immune-inflammatory pathways, cytokine production, Toll-Like Receptor signalling, with a major involvement of the PI3K-Akt pathway. Analyses of the downregulated CNS genes suggest electron transport chain dysfunctions at multiple levels. Network topological analyses revealed that the consequent aberrations in axonogenesis, neurogenesis, synaptic transmission, and regulation of transsynaptic signalling affect neurodevelopment with subsequent impairments in social behaviours and neurocognition. The results suggest a defense response against viral infection. CONCLUSIONS: Peripheral activation of immune-inflammatory pathways, most likely induced by viral infections, may result in CNS neuroinflammation and mitochondrial dysfunction, leading to abnormalities in transsynaptic transmission, and brain neurodevelopment.
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spelling pubmed-102757032023-06-17 Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment Gevezova, Maria Sbirkov, Yordan Sarafian, Victoria Plaimas, Kitiporn Suratanee, Apichat Maes, Michael Brain Behav Immun Health Full Length Article BACKGROUND: Despite advances in autism spectrum disorder (ASD) research and the vast genomic, transcriptomic, and proteomic data available, there are still controversies regarding the pathways and molecular signatures underlying the neurodevelopmental disorders leading to ASD. PURPOSE: To delineate these underpinning signatures, we examined the two largest gene expression meta-analysis datasets obtained from the brain and peripheral blood mononuclear cells (PBMCs) of 1355 ASD patients and 1110 controls. METHODS: We performed network, enrichment, and annotation analyses using the differentially expressed genes, transcripts, and proteins identified in ASD patients. RESULTS: Transcription factor network analyses in up- and down-regulated genes in brain tissue and PBMCs in ASD showed eight main transcription factors, namely: BCL3, CEBPB, IRF1, IRF8, KAT2A, NELFE, RELA, and TRIM28. The upregulated gene networks in PBMCs of ASD patients are strongly associated with activated immune-inflammatory pathways, including interferon-α signaling, and cellular responses to DNA repair. Enrichment analyses of the upregulated CNS gene networks indicate involvement of immune-inflammatory pathways, cytokine production, Toll-Like Receptor signalling, with a major involvement of the PI3K-Akt pathway. Analyses of the downregulated CNS genes suggest electron transport chain dysfunctions at multiple levels. Network topological analyses revealed that the consequent aberrations in axonogenesis, neurogenesis, synaptic transmission, and regulation of transsynaptic signalling affect neurodevelopment with subsequent impairments in social behaviours and neurocognition. The results suggest a defense response against viral infection. CONCLUSIONS: Peripheral activation of immune-inflammatory pathways, most likely induced by viral infections, may result in CNS neuroinflammation and mitochondrial dysfunction, leading to abnormalities in transsynaptic transmission, and brain neurodevelopment. Elsevier 2023-06-05 /pmc/articles/PMC10275703/ /pubmed/37334258 http://dx.doi.org/10.1016/j.bbih.2023.100646 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Full Length Article
Gevezova, Maria
Sbirkov, Yordan
Sarafian, Victoria
Plaimas, Kitiporn
Suratanee, Apichat
Maes, Michael
Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title_full Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title_fullStr Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title_full_unstemmed Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title_short Autistic spectrum disorder (ASD) – Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
title_sort autistic spectrum disorder (asd) – gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment
topic Full Length Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10275703/
https://www.ncbi.nlm.nih.gov/pubmed/37334258
http://dx.doi.org/10.1016/j.bbih.2023.100646
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