Biology subjects

Ryding, M.

Publications and source records attributed to Ryding, M..

4 recordsLinked to original sources

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↗

bioRxiv2024

Temporal proteomic and PTMomic atlas of cerebral organoid development

Cerebral organoids (CBOs) are generated from pluripotent stem cells that undergo neuroectoderm specification and neuronal differentiation in three dimensions. The developing neurons in CBOs migrate and self-organize into cerebral cortex-like layers, mimicking human brain development. CBOs develop according to intrinsic signaling mechanisms and offer unique insights into mechanisms of early human brain development. This process requires coordinated spatiotemporal regulation of protein expression and function, where the latter can be achieved by post-translational modifications (PTMs) on proteins. Despite the importance of proteins in brain development and function, profiling of protein abundance and the involvement of PTMs in CBO development remain underexplored. To gain insight into protein and PTM abundance in CBOs, we performed a high-resolution temporal analysis of CBOs up to day 200 using proteomics, PTMomics and metabolomics. We quantified more than 9,300 proteins and various neurodevelopmentally relevant PTMs (including phosphorylation, lysine acetylation, sialylated N-glycosylation, and cysteine modifications). We demonstrate that protein abundance and dynamic PTMs show significant temporal changes during CBO development related to neuronal differentiation and energy metabolism, whereas calcium signaling is mainly regulated by dynamic PTMs. We further show that synaptic protein content correlated with neurotransmitter levels, and we detected astroglia beyond day 100. Lastly, comparative analysis showed proteomic similarities between CBOs and human fetal brain tissue, supporting the physiological relevance of CBOs. Overall, our study presents a temporal atlas of protein and PTM abundance in CBOs and provides a valuable resource for studying neurodevelopment in neural organoids.

neuroscience↗

bioRxiv2020

Investigation of anti-IgLON5-induced neurodegenerative changes in human neurons

Anti-IgLON5 disease is a progressive neurological disorder, associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human post-mortem brain tissue neurodegeneration and accumulation of phosphorylated-Tau is found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response remains to be elucidated. To clarify this, we exposed human stem cell derived neurons to patient anti-IgLON5 antibodies. Human neural stem cells were differentiated for 14-48 days, and exposed from day 9-14, or day 13-48 to either 1) IgG from a patient with confirmed anti-IgLON5 antibodies; 2) IgG from a healthy person or left untreated. Electrical neuronal activity was quantified using a multi electrode array. Cultures were immunostained for {beta}-tubulin III, phosphorylated-Tau and counterstained with DAPI. Other cultures were immunostained for synaptic proteins PSD95 and synaptophysin. Lactate dehydrogenase release and nuclei morphology analyses were performed to assess cell viability. Spike rates and quantity of synaptic clusters were significantly reduced in anti-IgLON5 exposed cultures, and the proportion of cells with degenerative appearance was significantly higher for the anti-IgLON5 IgG group. Furthermore, the content of cells displaying accumulation of phosphorylated-Tau was higher for anti-IgLON5 exposed cultures. After five weeks, cultures exposed to anti-IgLON5 IgG contained significantly more dying cells. In conclusion, exposure of human neurons to pathological anti-IgLON5 antibodies cause functional impairment, synaptic and neurodegenerative changes, ultimately leading to cell death. This supports autoantibodies as a causative factor responsible for the neurodegenerative changes seen in patients with anti-IgLON5 disease and mimics pathological observations.

neuroscience↗

bioRxiv2019

Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

Mutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinsons disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, {beta}-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.

neuroscience↗