Geddes, V. E. V. | Search bioRxiv

bioRxiv2026

Integrated multiomic profiling of SCN2A loss-of-function reveals widespread molecular remodeling in patient hiPSC-derived neurons

SCN2A-related neurodevelopmental disorders comprise a genetically and mechanistically diverse group of early-onset brain conditions. Loss-of-function (LoF) variants in SCN2A represent one of the strongest genetic risk factors for autism spectrum disorder and intellectual disability, yet the molecular cascade linking reduced NaV1.2 dosage to neuronal dysfunction remains poorly understood. Here, we combine deep isoform-resolved transcriptomics, high-content imaging, and high-content cellular phenotyping in human hiPSC-derived neurons from three unrelated individuals carrying pathogenic SCN2A LoF variants and three independent healthy donor lines to delineate the multi-layered consequences of NaV1.2 insufficiency. We show that SCN2A LoF activates the nonsense-mediated decay (NMD) mechanism, selectively depleting canonical SCN2A isoforms and modifying the cells RNA processing. These molecular deficits translate into robust structural phenotypes, including axon initial segment shortening, reduced sodium channel density, and simplified dendritic arborization. Transcriptomic analysis converged on remodeling of synaptic and axonal pathways. RNA-seq identified coordinated alterations in gene programs linked to synaptic signaling, ion channel activity, and neuronal projection development, consistent with the structural and functional phenotypes observed. Transcript-level analysis further uncovered extensive perturbation of long non-coding RNA (lncRNA) networks, including lncRNAs strongly correlated with SYN1 and ANK3 isoforms. Together, these findings reveal that SCN2A haploinsufficiency induces a phenotype spanning NMD activation, isoform-specific dysregulation, axon initial segment destabilization and lncRNA-dependent regulatory shifts. This multiscale framework clarifies how reduced NaV1.2 disrupts neuronal development and highlights isoform-level restoration and modulation of post-transcriptional control as promising therapeutic avenues for SCN2A-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Microcephaly-like phenotype triggered by novel reassortant and prototypic Oropouche Virus strains in brain organoids

Oropouche virus (OROV) is an emerging arbovirus currently spreading across South America, with increasing reports of neurological manifestations, severe systemic disease, and congenital abnormalities. Although traditionally associated with mild febrile illness, the recent geographic expansion and surge in OROV outbreaks have prompted attention to its neurotropic potential. Here, we investigated the impact of OROV infection on human neural development using neural stem cells (NSCs) and brain organoids derived from induced pluripotent stem cells. Recent OROV isolates exhibiting genomic reassortment and associated with increased neurological manifestations were compared with a prototypical strain for the ability to infect NSCs, early-stage organoids, and more mature cortical-like tissues. OROV infected NSCs efficiently, leading to widespread cell death, depletion of proliferative progenitors, and disruption of neuroepithelial organization. Transcriptomic profiling of infected NSCs revealed a robust reduction of antiviral response genes and an enrichment of pathways related to viral replication, apoptosis, and the inhibition of stem cell maintenance and neuronal differentiation. These molecular signatures aligned with the phenotypic collapse of progenitor pools and cortical structure observed in organoids. OROV antigens were detected in both astrocytes and neurons, with associated structural degeneration. Although a substantial overlap in differentially expressed genes was observed between the two viral strains, some strain-specific transcriptional responses were detected. However, these modest differences did not translate into distinct cytopathogenic effects between the two viral strains. These phenotypes, including the reduced growth of infected organoids, resemble those previously described with Zika virus in the same cellular models, supporting the hypothesis that OROV may impair brain development. Together, these results reveal a previously unrecognized neuroteratogenic potential of OROV strains and provide mechanistic insight into the potential of OROV to induce microcephaly-like phenotypes, highlighting its relevance as a significant threat to maternal-fetal health.

neuroscience↗