Biology subjects

Parent, J.

Publications and source records attributed to Parent, J..

5 recordsLinked to original sources

bioRxiv2026

A CK2α-G3BP1 signaling axis regulates local translation in developing neurons and is disrupted in OCNDS

Neurodevelopmental disorders are frequently caused by mutations in pleiotropic kinases, yet downstream effectors driving neuronal pathology remain undefined. Here, we identify the G3BP1-dependent stress granule pathway as the dominant effector of casein kinase 2 (CK2) in developing neurons, implying that its dysregulation underlies the neurodevelopmental deficits of Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS-associated CK2 mutations reduce phosphorylation of G3BP1 at serine 149, promoting aberrant phase separation and persistent granules that sequester neuronal mRNAs and suppress local protein synthesis across axonal and dendritic compartments. These phenotypes produce allele-specific deficits in neuronal morphogenesis, synaptic abundance, and network excitability, which are conserved in a knock-in mouse model and in patient-derived iPSC neurons. G3bp1 knockdown rescues translational and morphological phenotypes across all OCNDS alleles, demonstrating that restoring granule homeostasis reverses neuronal pathology. Together, these findings establish OCNDS as a disorder of compartment-specific translational dysregulation driven by impaired CK2-G3BP1 control of RNA granule homeostasis. SummaryOCNDS mutations disrupt CK2-G3BP1 signaling, causing persistent granules and defective neuronal translation and development.

neuroscience↗

bioRxiv2026

Progenitor Diversity and Architecture of the Human Ganglionic Eminences Shaping the Basal Ganglia

The embryonic medial and lateral ganglionic eminences (MGE, LGE) are the principal sources of most neurons and glia for the basal ganglia. In primates, the MGE has a distinctive cytoarchitecture characterized by doublecortin enriched cellular nests (DENs), yet the architectonic organization underlying DEN formation, the molecular heterogeneity of ganglionic eminence progenitors and their lineage relationships, remain poorly understood. Here, using paired single-nucleus transcriptomics and chromatin accessibility profiling of the three GEs, we identify distinct progenitor populations, delineate their gene regulatory networks, and reconstruct their lineage trajectories. Live imaging reveals a unipolar outer radial glia-like population (GE-oRG) that undergoes mitotic somal translocation. Spatial transcriptomics identifies a distinct CRABP1+/ANGPT2+ domain within the MGE. Integrated spatial and electron microscopy demonstrates a periphery-to-center gradient of differentiation in the MGE. Leveraging DEN-forming MGE organoids derived from PCDH19 knockout human pluripotent stem cell lines, we identify the protocadherin, PCDH19, as a key regulator of DEN formation.

neuroscience↗

bioRxiv2025

EpiPred: A gene-specific machine learning model for classifying missense variants in the epilepsy-related gene STXBP1

Missense variants in the STXBP1 gene are a frequent cause of early-onset developmental and epileptic encephalopathies and related neurodevelopmental disorders, but the clinical interpretation of these variants remains a major challenge. Most reported STXBP1 missense variants are classified as variants of uncertain significance (VUS), complicating diagnosis, counseling, and patient eligibility for precision therapies. Here, we developed EpiPred, a gene-specific machine learning classifier that predicts the pathogenicity of STXBP1 missense variants by integrating computational features with empirical evidence from cellular assays. Trained on a curated set of pathogenic and benign variants, EpiPred outperformed leading global prediction tools in accuracy, sensitivity, and specificity. We validated the models predictions using functional assays that measure protein abundance, solubility, stability, and interaction with the SNARE complex partner syntaxin 1. These biochemical readouts aligned closely with model outputs and enabled reclassification of several likely misdiagnosed variants. We deployed EpiPred in an interactive web application that allows clinicians, researchers, and patients to explore predictions for all possible missense variants in STXBP1. Our approach illustrates the power of gene-specific predictive modeling combined with experimental validation to improve variant interpretation and diagnostic resolution. By identifying likely pathogenic STXBP1 variants, including those that may respond to emerging therapies such as molecular chaperones, EpiPred supports more precise genetic diagnoses and offers a generalizable framework for other clinically relevant genes in neurological disease. ONE SENTENCE SUMMARYEpiPred improves STXBP1 variant interpretation, enabling precision genetic diagnoses and promoting access to targeted precision therapies

genetics↗

bioRxiv2024

Modeling Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- and hippocampal-ganglionic eminence assembloids to model Developmental and Epileptic Encephalopathy 13 (DEE-13), a condition arising from gain-of-function mutations in the SCN8A gene. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.

neuroscience↗

bioRxiv2018

Targeted Reactivation of FMR1 Transcription in Fragile X Syndrome Embryonic Stem Cells

Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability and autism. It results from expansion of a CGG nucleotide repeat in the 5 untranslated region of FMR1. Large expansions elicit repeat and promoter hyper-methylation, heterochromatin formation, FMR1 transcriptional silencing, and loss of the Fragile X protein, FMRP. Efforts aimed at correcting the sequelae resultant from FMRP loss have thus far proven insufficient, perhaps because of FMRPs pleiotropic functions. As the repeats do not disrupt the FMRP coding sequence, reactivation of endogenous FMR1 gene expression could correct the proximal event in FXS pathogenesis. Here we utilize the CRISPR/dCAS9 system to selectively re-activate transcription from the silenced FMR1 locus. Fusion of the transcriptional activator VP192 to dCAS9 robustly enhances FMR1 transcription and increases FMRP levels when targeted directly to the CGG repeat in human cells. Using a previously uncharacterized FXS human embryonic stem cell (hESC) line which acquires transcriptional silencing with serial passaging, we achieved locus-specific transcriptional re-activation of FMR1 mRNA expression despite promoter and repeat methylation. These studies demonstrate that FMR1 mRNA expression can be selectively reactivated in human patient cells, creating a pathway forward for therapeutic development in Fragile X Syndrome.

neuroscience↗