Biology subjects

El Soufi El Sabbagh, D.

Publications and source records attributed to El Soufi El Sabbagh, D..

3 recordsLinked to original sources

bioRxiv2026

The toll-like receptor signalling pathway is altered in iPSC-derived cortical networks from people with bipolar disorder.

BackgroundInduced pluripotent stem cell (iPSC)-derived brain cells are widely utilized as in vitro models for several neuropsychiatric disorders, as they retain the donors genetic profile, offering a unique opportunity to study living human brain cells and perform controlled experimental manipulations. In this study, we conducted whole transcriptome sequencing of cortical networks (co-cultures of neurons and astrocytes) derived from 12 participants with bipolar disorder (BD) and 12 participants without a history of mental health disorders. We aimed to identify new molecular mechanisms underlying the pathophysiology of bipolar disorder. MethodsiPSCs were generated by reprogramming peripheral blood mononuclear cells using episomal vectors. They were then differentiated into neural progenitor cells and matured into cortical networks that express markers of neurons and astrocytes. Whole transcriptome data were obtained using the Illumina NovaSeq X sequencing platform. ResultsDifferential expression analysis was performed using DESeq2 in R, and the identified genes were used for gene set enrichment analysis, which identified 191 enriched pathways in BD. Of these, the toll-like signalling pathway, which is downregulated in BD, was further investigated. ConclusionOur results suggest a profound immune dysregulation in BD, particularly highlighting the immune systems role as a complex signalling network.

neuroscience↗

bioRxiv2025

From iPSCs to NPCs to cortical neurons: bioenergetic, neuronal, and calcium signaling phenotypes in bipolar disorder with and without familial mitochondrial disease

BackgroundPsychiatric disorders frequently accompany primary mitochondrial diseases (PMDs), implicating mitochondrial dysfunction as a shared biological substrate for psychiatric vulnerability. To determine how familial mitochondrial risk influences neuronal development in bipolar disorder (BD), we generated induced pluripotent stem cells (iPSCs), neural progenitor cells (NPCs), and cortical neurons (CNs) from three healthy controls (CT), three patients with BD, and three patients with BD and a family history of mitochondrial disease (BD-FMD). MethodsAcross differentiation, we assessed mitochondrial function (ATP production, mitochondrial membrane potential, ROS generation, cytosolic cell-free mtDNA), metabolomic signatures, calcium imaging, and neuronal electrophysiological activity through multi-electrode arrays (MEA). ResultsBD neurons uniquely exhibited pronounced hyperexcitability in comparison to CT and BD-FMD groups. The BD-FMD group displayed prolonged mitochondrial calcium transients, altered membrane potential, and aberrant ROS, in comparison to CT and BD, consistent with a sustained energetic deficit. Metabolomic profiling revealed distinct pathway enrichments in BD and BD-FMD, indicating divergent bioenergetic adaptations to mitochondrial burden. ConclusionsOur findings reveal that familial mitochondrial liability actively reshapes neuronal differentiation and function, producing distinct trajectories of mitochondrial performance, calcium signaling, and network excitability. These results suggest that mitochondrial dysfunction in BD is not a secondary byproduct of illness, but a mechanistic contributor to altered neuronal energetics and communication. Together, these findings delineate how inherited mitochondrial vulnerability reshapes neuronal excitability and metabolism, revealing bioenergetic phenotypes that may inform precision stratification and therapeutic targeting in BD.

neuroscience↗

bioRxiv2025

iPSC-Derived Cerebral Organoids Reveal Mitochondrial, Inflammatory and Neuronal Vulnerabilities in Bipolar Disorder

Bipolar disorder (BD) is increasingly recognized as a disorder with both mitochondrial dysfunction and heightened inflammatory reactivity, yet their contribution to neuronal activity remains unclear. To address these gaps, this study utilizes iPSC-derived cerebral organoids (COs) from BD patients and healthy controls to model disease-specific metabolic and inflammatory dysfunction in a physiologically relevant system. BD COs exhibited mitochondrial impairment, dysregulated metabolic function, and increased nod-leucine rich repeat and pyrin domain containing protein 3 (NLRP3) inflammasome activation sensitivity. Treatment with MCC950, a selective NLRP3 inhibitor, effectively rescued mitochondrial function and reduced inflammatory activation in both BD and control COs. Additionally, a Bioactive Flavonoid Extract (BFE) was explored as a potential therapeutic, demonstrating partial rescue of inflammasome activation. These findings highlight a mitochondria-inflammasome axis in BD pathophysiology and establish a novel platform for studying BD-associated cellular mechanisms, ultimately bridging the gap between molecular dysfunction and therapeutic development.

neuroscience↗