Systems biology and single-cell transcriptome analysis identify potential therapeutic targets and impaired neurogenesis in human cortical development related to autism spectrum disorder.

内容摘要

Autism Spectrum Disorder (ASD) has been linked to disturbance of the coordinated transcriptional mechanisms that govern neurogenesis, neuronal differentiation, and synaptic maturation in human cortical development. Nevertheless, the regulatory networks and cellular heterogeneity that underlie these processes are still poorly understood. Using an in vitro human cortical development dataset (GSE210960), single-cell RNA sequencing (scRNA-seq) and systems biology techniques were used to examine neurodevelopmental pathways associated with ASD. Different cellular populations representing neural progenitors and differentiated neuronal states were resolved by Seurat-based preprocessing and clustering, and developmental progressions from progenitor cells towards adult neuronal lineages were recreated using trajectory inference. Key biological processes linked to RNA splicing, energy consumption, and the formation of neural projections were found by differential expression and gene set enrichment analysis. Highly connected hub genes, such as RACK1 and NRXN1, which are essential for synaptic signalling and neuronal development and have been linked to an increased risk of ASD, were given priority in protein-protein interaction network analysis. Stable binding of tretinoin (all-trans-retinoic acid) to RACK1 was discovered by virtual drug screening, molecular docking, and molecular dynamics simulations. This was corroborated by favourable docking scores and persistent conformational stability across a 100 ns simulation. All things considered, these results offer a systems-level single-cell transcriptomic framework for locating potential molecular targets and neurodevelopmental pathways related to ASD.