Biology subjects

Michalski, C.

Publications and source records attributed to Michalski, C..

5 recordsLinked to original sources

bioRxiv2026

Synaptic microRNA dysregulation orchestrates aberrant glutamatergic transmission in a human neuronal model of 22q11.2 deletion syndrome

22q11.2 Deletion Syndrome (22q11DS), the most prevalent chromosomal microdeletion disorder in humans (incidence ~1 in 4,000 live births), arises from hemizygous deletions of a 1.5-3.0 Mb region on chromosome 22. Notably, 20-30% of individuals with 22q11DS develop schizophrenia (SCZ) by early adulthood, making 22q11DS one of the strongest genetic risk factors for SCZ. However, the mechanisms by which the 22q11.2 deletion perturbs neuronal function and drive psychotic manifestations in 22q11DS remain poorly defined. In this study, we generated human 2D cortical neurons and 3D cortical organoids from induced pluripotent stem cells (iPSCs) derived from clinically well-characterized individuals with 22q11DS. Cellular and electrophysiological analyses revealed that 22q11DS neurons exhibit hyperexcitability, reduced glutamatergic synaptic transmission, and impaired homeostatic synaptic plasticity, which are pathophysiological hallmarks that may be relevant to the clinical, cognitive, and psychophysiological profiles of patients. Transcriptomic profiling of neurons and synaptosomes from 22q11DS cortical organoids uncovered dysregulated immune pathways and synaptic gene networks. Integrative mRNA-microRNA network analysis identified synergistic downregulation of hsa-miR-185-5p and hsa-miR-128-3p at synapses, driving aberrant regulation of immune and synaptic transcripts. Experimental knockdown of these microRNAs in control neurons recapitulated the molecular and functional phenotypes of 22q11DS neurons, thereby establishing a mechanistic link to synaptic dysfunction and impaired plasticity. Collectively, these findings delineate a multimodal mechanistic framework that bridges genetic vulnerability, synaptic pathology, and psychosis penetrance in 22q11DS, positioning dysregulated synaptic microRNAs as nodal regulators of neurodevelopmental networks and potential therapeutic targets.

neuroscience↗

bioRxiv2025

Pancreatic cancer patient-derived organoids capture therapy response and tumor evolution

Patient-derived organoids (PDOs) reflect parental tumor features and may represent promising avatars for prognosticating drug response. Here, we recruited 169 patients with pancreatic cancer (PC) and established a living biobank including 83 pharmacotyped PDOs isolated from primary and metastatic, treatment-naive and pretreated PCs. In a core facility setting, the pharmacotyping success rate was 61.5%, with an unmet turnaround time of 32 days. Forty-six patients who underwent a total of 94 therapeutic lines were analyzed, resulting in a pharmacotyping-patient response matching rate of 73.4%. Sensitivity, specificity, positive and negative predictive values were 85.0%, 64.8%, 64.2%, and 85.4%, respectively. Tracing clonal evolution in longitudinal biopsies uncovered therapy-induced genetic alterations and single-nucleus multiomics identified transcriptomic and epigenetic changes associated with abnormal FGF signaling during treatment in one particular tracked study case. Our findings highlight the potential of PDOs as robust tools for drug response prediction and patient modeling to advance functional precision medicine.

cancer biology↗

bioRxiv2024

Longitudinal multi-omics reveals pathogenic TSC2 variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is caused by heterozygous mutations in either the TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes affect the longitudinal trajectory of human brain development remains largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 variants, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analyses of TSC organoids, we found that TSC2 pathogenic variants dysregulate neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Intriguingly, single cell transcriptomic analyses on TSC organoids revealed that TSC2 pathogenic variants disrupt the neuron/reactive astrocyte crosstalk within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomic analyses of synaptosomes, demonstrated that the TSC2 variants precipitate perturbations in synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation. Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associated TSC2 variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.

neuroscience↗

bioRxiv2024

Nutrient Sensing Receptor GPRC6A Regulates mTORC1 Signaling and Tau Biology

Tauopathies, including Alzheimers disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. Significance StatementTauopathies, including Alzheimers disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.

neuroscience↗

bioRxiv2020

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC. In-silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depth in-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

genetics↗