Autistic spectrum disorder (ASD) - Gene, molecular and pathway signatures linking systemic inflammation, mitochondrial dysfunction, transsynaptic signalling, and neurodevelopment.
Brain Behav Immun Health
; 30: 100646, 2023 Jul.
Article
en En
| MEDLINE
| ID: mdl-37334258
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Brain Behav Immun Health
Año:
2023
Tipo del documento:
Article
País de afiliación:
Bulgaria