Biology subjects

Bayram, E.

Publications and source records attributed to Bayram, E..

4 recordsLinked to original sources

bioRxiv2026

Patient-Derived Air-Liquid Interface Forebrain Organoids Reveal Functional Synaptic Deficits in Schizophrenia

Schizophrenia (SCZ) is a severe and debilitating neurodevelopmental disorder with lifelong impact on everyday life. Disruptions in synapse functions play a key role in its complex and poorly understood etiological and pathological mechanisms. Here, we investigated both the molecular composition and the spontaneous and stimulated functional properties of synapses in neural organoids from SCZ individuals. Air-liquid interface forebrain organoids (ALI-FOs) were generated from induced pluripotent stem cells (iPSCs) derived from three individuals with SCZ and three healthy controls. At day 170 synaptosomes were enriched and analyzed by data-independent acquisition mass spectrometry to profile the proteome, alongside with TMT-labeled phosphoproteomics both before and after acute KCl-induced depolarization. In parallel, we characterized the PTMome of the surrounding cellular environment, comprising phosphorylation, peptides with free and reversibly modified cysteines, and sialylated N-linked glycopeptides. Functional glutamatergic and GABAergic activity was assessed using calcium imaging to capture spontaneous neuronal signaling. Both conditions exhibited mature synaptic structures, while growth cones were observed only in SCZ-derived ALI-FOs, indicative of ongoing or delayed synaptogenesis. Proteomic analysis of synaptosome preparations revealed 358 differentially regulated proteins between SCZ and controls and 125 phophoproteins with altered phosphorylation, which clustered into three major categories: (1) synaptogenesis and synapse signaling; (2) cytoskeleton and cell junctions; (3) growth cone dynamics and neurite outgrowth. Analysis of the PTMs in the surrounding cellular environment revealed regulation of key regulatory mechanisms in 526 proteins, supporting the synaptic alterations observed. Notably, components of the Wnt signaling pathway were consistently dysregulated across both the synaptosome preparation and the PTMome in SCZ-derived ALIFOs as compared to controls. Depolarization-induced phospho-signaling revealed SCZ-specific response enriched in synaptic vesicle trafficking pathways. Together, these findings provide new insights into early synaptic alterations in SCZ, highlighting changes not only in protein composition, but more in protein regulatory mechanisms underlying synaptic signaling.

neuroscience↗

bioRxiv2026

Protein-state dysregulation and sex-specific neurodevelopmental signatures in schizophrenia forebrain organoids

Schizophrenia is highly heritable, yet the molecular mechanisms linking genetic risk to abnormal human brain development remain poorly understood. To address this, we generated dorsal forebrain organoids from 17 individuals with idiopathic schizophrenia and 17 age- and sex-matched controls and profiled them across multiple molecular layers, including single-nucleus transcriptomics, quantitative proteomics, metabolomics and deep post-translational modification (PTM) analysis. The organoids reproducibly modelled early cortical development and showed largely similar cellular composition between schizophrenia and control groups. Surprisingly, transcriptomic differences were relatively limited, with the strongest cell-type-specific changes observed in Cajal-Retzius neurons. In contrast, proteomic and particularly PTM-level analyses revealed widespread molecular disruption affecting pathways involved in neuronal migration, neurite development, synaptic function, protein kinase signalling, extracellular matrix organisation and lipid metabolism. Many of the earliest disease-associated changes emerged at the level of protein phosphorylation, consistent with altered neuronal maturation and neurite dynamics. At later developmental stages, schizophrenia organoids showed reduced abundance of synaptic proteins, fewer synaptic puncta and evidence of dysregulated retinoic acid and YAP1 signalling. Notably, most disease-associated alterations occurred independently of changes in transcript or protein abundance, indicating that key aspects of schizophrenia biology are encoded in protein state rather than expression level. These findings identify sex-specific dysregulation of protein state as a major molecular feature of schizophrenia and demonstrate the value of multi-layer proteomic approaches for uncovering disease mechanisms missed by transcriptomics alone.

neuroscience↗

bioRxiv2026

Dysregulation of miRNAs Drives Premature GABAergic Maturation and Early Neurodevelopmental Defects in Schizophrenia

BackgroundSchizophrenia (SCZ) is a severe neurodevelopmental disorder with numerous genetic risk loci. However, little is known about the molecular alterations that occur during brain development in SCZ, particularly regarding the role of microRNA (miRNA) mediated regulatory mechanisms. This gap in knowledge is largely due to the limited availability of developing human brain tissue. Patient-derived brain organoids offer a promising alternative model. Here we use 3D dorsal forebrain organoids (DFOs) to investigate miRNA dysregulation in SCZ. MethodsDFOs were generated from human induced pluripotent stem cells (hiPSCs) derived from six SCZ patients and five matched controls and cultured for 120 days. Multi-omics analyses, immunohistochemistry, and in situ hybridization were employed to characterize molecular and spatial features. ResultsDFOs recapitulated key molecular hallmarks of human cortical development. Nineteen miRNAs were differentially expressed in SCZ: nine associated with neural progenitor proliferation were downregulated and ten linked to neuronal differentiation and synaptic maturation were upregulated, reflecting a compressed developmental timeline. Among 77 dysregulated mRNAs, 55 were predicted miRNA targets. SCZ DFOs exhibited significant upregulation of GABAergic pathway genes accompanied by altered expression of their regulatory miRNAs, indicating premature GABAergic lineage specification. The disrupted miRNA-mRNA network converged on glutamatergic and dopaminergic development, synaptic organization, and extracellular matrix remodeling. ConclusionDysregulated miRNAs in SCZ DFOs disrupt neuronal differentiation, excitatory-inhibitory balance, and early circuit formation, implicating miRNA-mediated post-transcriptional regulation as a key mechanism linking molecular alterations to cellular and network-level deficits in SCZ.

cell biology↗

bioRxiv2024

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

INTRODUCTIONSex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODSParticipants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTSWhile sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants. DISCUSSIONIn genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.

neuroscience↗