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Abstract Details

Cross-disease Transcriptomic Analysis Elucidating the Roles of Astrocytic Signaling Pathways Regulating Neuroinflammation in Autism Spectrum Disorder
Child Neurology and Developmental Neurology
S2 - Child Neurology and Developmental Neurology 1 (1:24 PM-1:36 PM)
003
While neuroinflammation has been implicated as a major component in autism spectrum disorder (ASD) and its etiology, the molecular mechanism in the disease is not well understood. Advances in single-cell genomics and transcriptomics have fueled the identification of novel pathways that control astrocyte functions associated with chronic neuroinflammatory disorders such as multiple sclerosis (MS). These advances present an opportunity to study the common molecular mechanisms involved in both ASD and MS, and ultimately elucidate ASD etiology.

This research aims to elucidate the roles of astrocytic signaling pathways regulating neuroinflammation in autism spectrum disorder.

In this paper, we analyze and characterize the common astrocytes subpopulations shared in both ASD and MS using the large-scale single-cell RNA-seq expression data collected from postmortem brain samples of subjects diagnosed with ASD (PRJNA434002) and MS (PRJNA544731). Batch correction was implemented using Harmony to strengthen the unbiased analysis. Seurat and SC3 were used for the identification of common astrocyte clusters and their marker genes; DESeq2 for disease-specific differential expressed gene (DEG) analysis; Monocle and Enrichr for trajectory and ingenuity pathway analysis (IPA) of DEGs. Finally, GSEA was performed on IPSC bulk-RNA sequencing data to further characterize the common pro-inflammatory astrocytes subpopulations using secondary progressive stage transcriptional signatures of MS.

This research identified two astrocyte subpopulations common to ASD and MS. Our analysis revealed that oxidative stress-mediated ferroptosis plays a pronounced role in the pathological astrocyte subpopulations. This discovery enables us to hypothesize that FTH1, SLC7A11, SAT1, CP, FTL and MAPK signaling are potentially involved in ASD pathophysiology, which could be further explored as novel targets for intervention.

Linking transcriptionally-defined astrocyte subpopulations cross diseases could yield better understanding of their roles in each disease-specific context. Inflammation-promoting oxidative stress-mediated ferroptosis should be further studied for its roles in the pathological astrocyte subpopulations in ASD.

Authors/Disclosures
Valentina Zhang, Other
PRESENTER
Miss Zhang has nothing to disclose.