Biology subjects

Schmidt, S. I.

Publications and source records attributed to Schmidt, S. I..

5 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↗

bioRxiv2025

Quantifying the effect of groundwater fauna and temperature on the ecosystem service of microbial carbon degradation

Groundwater ecosystems fulfil functions that humankind relies upon, e.g. for sustainable drinking water production. Quantification of these services is lacking so far. Thus, it is not possible to predict scenarios (e.g. future climates). Based on data from a comprehensive groundwater ecosystem study comprising four zones of varying land use and groundwater / surface water exchange, we parameterized a quantitative dynamic food web model (recharged organic carbon, microorganisms using the biodegradable fraction of this carbon, and fauna grazing on the microorganisms). With the model satisfactorily reflecting the field data, we calculated five further scenarios, three of which without fauna (mortality e.g. due to contamination, sudden peaks of temperature etc.). Two of the "fauna" and two of the "no fauna" scenarios were run with temperature elevated by 1.5{degrees}C and 3{degrees}C, respectively. The ecosystem service of carbon degradation was expressed as the difference in carbon concentration between the beginning of the simulation and the end of the simulation. In most scenarios, remaining carbon increased over time. The remaining carbon in some scenarios was up to 6.6 times as high in the "no fauna" scenarios compared to the reference case. Fauna was thus shown to fulfil a service by promoting microbial carbon degradation that may be substantial. Sustainable drinking water production is more reliable and less costly, the more active the groundwater fauna in the production area is. This model set up can serve to test other cases of varying physical and chemical variations and disturbances.

ecology↗

bioRxiv2023

Direct and indirect effects of the increase in atmospheric CO2 and temperature on groundwater organisms

Atmospherically rising temperature and CO2 impact all freshwater systems, including groundwater. Increasing CO2 leads to more intense weathering of silicate rocks. Here, we tested whether the increased levels, the weathering, or rather the increasing temperature, impacted on fauna and prokaryotes in the groundwater ecosystem. We conducted the analyses separately for deep, i.e. secluded, and shallow, quaternary aquifers which exchange with the surface more intensely. Organism abundances and relative composition did not correlate with temperature or CO2 levels. While many organisms rely on silica, in contrast, we found negative correlations between silica and fauna. The increases in silica over time, i.e. temporal trends, also partly correlated negatively with organisms. We hypothesize that the unexpected negative correlations are not direct effects, but indirectly indicate that groundwater communities do not adapt rapidly enough to changes. This jeopardizes future drinking water production which relies on the self-cleaning ecosystem services in groundwater.

ecology↗

bioRxiv2021

Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

Accumulation of aggregated alpha-synuclein (-syn) is believed to play a pivotal role in the pathophysiology of Parkinsons disease (PD) and other synucleinopathies. -Syn is a key constituent protein of Lewy pathology, and -syn phosphorylated at serine-129 (pS129) constitutes more than 90% of -syn in Lewy bodies and hence, it is used extensively as a pathological marker for the aggregated form of -syn. However, the exact role of pS129 remains controversial as well as the kinase(s) responsible for the phosphorylation. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using ex-vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on -syn aggregation, pS129 or inter-neuronal spreading of the aggregated -syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble nuclear pS129 level confined in the nuclei. The same finding was replicated in an in-vivo mouse models of templated -syn aggregation and human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129 phosphorylation of soluble non-pathology related fraction of -syn. We also demonstrated that reduction of nuclear pS129 but not the aggregates specific pS129 following PLK2 inhibition for a short time before sample collection improves the signal to noise ratio when quantifying pS129 aggregate pathology.

neuroscience↗