Biology subjects

Wen, Z.

Publications and source records attributed to Wen, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Stereopy: modeling comparative and spatiotemporal cellular heterogeneity via multi-sample spatial transcriptomics

Tracing cellular dynamic changes across conditions, time, and space is crucial for understanding the molecular mechanisms underlying complex biological systems. However, integrating multi-sample data in a unified and flexible way to explore cellular heterogeneity remains a major challenge. Here, we present Stereopy, a flexible and versatile framework for modeling and dissecting comparative and spatiotemporal patterns in multi-sample spatial transcriptomics with interactive data visualization. To optimize this flexible framework, we have developed three key components: a multi-sample tailored data container, a scope controller, and an analysis transformer. Furthermore, Stereopy showcases three transformative applications supported by pivotal algorithms. Firstly, the multi-sample cell community detection (CCD) algorithm introduces an innovative capability to detect specific cell communities and identify genes responsible for pathological changes in comparable datasets. Secondly, the spatially resolved temporal gene pattern inference (TGPI) algorithm represents a notable advancement in detecting important spatiotemporal gene patterns while concurrently considering spatial and temporal features, which enhances the identification of important genes, domains and regulatory factors closely associated with temporal datasets. Finally, the 3D niche-based regulation inference tool, named NicheReg3D, reconstructs the 3D cell niches to enable the inference of cell-gene interaction network within the spatial texture, thus bridging intercellular communications and intracellular regulations to unravel the intricate regulatory mechanisms that govern cellular behavior. Overall, Stereopy serves as both a bioinformatics toolbox and an extensible framework that provides researchers with enhanced data interpretation abilities and new perspectives for mining multi-sample spatial transcriptomics data.

bioinformatics↗

bioRxiv2023

Instant Assembly of Collagen for Scaffolding, Tissue Engineering, and Bioprinting

Controllable assembly of cells and tissues offers potential for advancing disease and development modeling and regenerative medicine. The bodys natural scaffolding material is the extracellular matrix, composed largely of collagen I. However, challenges in precisely controlling collagen assembly limit collagens applicability as a primary bioink or glue for biofabrication. Here, we introduce a set of biopatterning methods, termed Tunable Rapid Assembly of Collagenous Elements (TRACE), that enables instant gelation and rapid patterning of collagen I solutions with wide range of concentrations. Our methods are based on accelerating the gelation of collagen solutions to instantaneous speeds via macromolecular crowding, allowing versatile patterning of both cell-free and cell-laden collagen-based bioinks. We demonstrate notable applications, including macroscopic organoid engineering, rapid free-form 3D bioprinting, contractile cardiac ventricle model, and patterning of high-resolution (below 5 (m) collagen filament. Our findings enable more controllable and versatile applications for multi-scale collagen-based biofabrication.

bioengineering↗

bioRxiv2023

Conservation of the ancestral function of GTSF1 in transposon silencing in unicellular Paramecium

The PIWI-interacting RNA (piRNA) pathway is crucial for transposon repression and the maintenance of genomic integrity. Gametocyte specific factor 1 (GTSF1), an indispensable auxiliary factor of PIWI, was recently shown to potentiate the catalytic activity of PIWI in many metazoans. Whether the requirement of GTSF1 extends to PIWI proteins beyond metazoans is unknown. In this study, we identified a homolog of GTSF1 in the unicellular eukaryote Paramecium tetraurelia (PtGTSF1) and found that its role as a PIWI-cofactor is conserved. PtGTSF1 interacts with PIWI (Ptiwi09) and Polycomb Repressive Complex 2 (PRC2) and is essential for PIWI-dependent DNA elimination of transposons during sexual development. PtGTSF1 is crucial for the degradation of PIWI-bound small RNAs recognizing the organisms own genomic sequences. Without PtGTSF1, self-matching small RNAs are not degraded and results in an accumulation of H3K9me3 and H3K27me3, which disturbs transposon recognition and slows down their elimination. Our results demonstrate that the PIWI-GTSF1 interaction also exists in unicellular eukaryotes with the ancestral function of transposon silencing.

cell biology↗

bioRxiv2023

Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase

Histone lysine methyltransferase of SUV420H1, which is responsible for site-specific di-/tri-methylation of histone H4 lysine 20 (H4K20), has crucial roles in DNA-templated processes, including DNA replication, DNA damage repair and chromatin compaction. Its mutations frequently occur in human cancers. Nucleosomes containing the histone variant H2A.Z enhance the catalytic activities of SUV420H1 in H4K20 di-methylation deposition, regulating early replication origins. However, the molecular mechanism of how H4K20 methyl marks are deposited on nucleosomes by SUV420H1 remains poorly understood. Here we report the cryo-electron microscopy (cryo-EM) structures of SUV420H1 associated with canonical nucleosome core particles (NCPs) or H2AZ containing NCPs. We find that SUV420H1 make extensive site-specific contacts with histone and DNA regions. SUV420H1 C-terminal domain recognizes the H2A-H2B acidic pocket of NCPs through its two arginine anchors, thus enabling H4K20 insertion for catalysis specifically. We also identify important residues increasing the catalytic activities of SUV420H1 bound to H2A.Z NCPs. In vitro and in vivo functional analysis reveal that multiple disease associated mutations at the interfaces are essential for its catalytic activity and chromatin states regulation. Together, our study provides molecular insights into the nucleosome-based recognition and methylation mechanisms of SUV420H1, and a structural basis for understanding SUV420H1-related human disease.

molecular biology↗

bioRxiv2023

Single-cell landscape reveals NAMPT mediated macrophage polarization that regulate smooth muscle cell phenotypic switch in pulmonary arterial hypertension

RationalePulmonary arterial hypertension (PAH) is a progressive and lethal disease that leads to elevated pulmonary vascular resistance and right ventricular failure. The phenotypic switching of pulmonary arterial smooth muscle cells (SMCs) plays a crucial role in the pathological progression of PAH. However, the underlying mechanism of SMC phenotypic modulation remains unclear. ObjectivesWe aim to provide a comprehensive understanding of SMC phenotypes and regulatory networks by analyzing hypertensive and non-diseased pulmonary arteries. MethodsWe performed single-cell RNA sequencing (scRNA-seq) on pulmonary arteries obtained from patients with PAH and healthy donors. This was followed by bioinformatics analyses, mouse models, and in vitro studies to construct a normal pulmonary artery atlas, characterize SMC phenotypes, investigate intercellular communication, and explore the molecular mechanisms underlying SMC phenotypic switching. Measurements and Main ResultsOur scRNA-seq analysis identified specific activation of vascular cells, including myofibrocytes, macrophage M2 polarization, endothelial-mesenchymal transition, and chondroid-like SMCs in healthy pulmonary arteries. In PAH pathology, there was an enhanced phenotypic switch of SMCs from contractile to fibroblast-like. Intercellular communication revealed increased M1 macrophage-SMC crosstalk in PAH, which was facilitated by NAMPT. Using a cellular co-culture system, we found that NAMPT-mediated M1 macrophage polarization induced fibroblast-like phenotypic switching in SMCs via the CCR2/CCR5 axis. ConclusionsOur findings provide a comprehensive cell atlas of healthy human pulmonary arteries and demonstrate that NAMPT-driven M1 macrophage polarization plays a critical role in the fibroblast-like phenotypic switching of SMCs through CCR2/CCR5 cellular crosstalk in PAH.

molecular biology↗

bioRxiv2023

Integrating Image and Molecular Profiles for Spatial Transcriptomics Analysis

The spatially resolved transcriptomics (SRT) field has revolutionized our ability to comprehensively leverage image and molecular profiles to elucidate spatial organization of cellular microenvironments. Current clustering analysis of SRT data primarily relies on molecular information and fails to fully exploit the morphological features present in histology images, leading to compromised accuracy and interpretability. To overcome these limitations, we have developed a multi-stage statistical method called iIMPACT. It includes a finite mixture model to identify and define histology-based spatial domains based on AI-reconstructed histology images and spatial context of gene expression measurements, and a negative binomial regression model to detect domain-specific spatially variable genes. Through multiple case studies, we demonstrate iIMPACT outperformed existing methods, confirmed by ground truth biological knowledge. These findings underscore the accuracy and interpretability of iIMPACT as a new clustering approach, providing valuable insights into the cellular spatial organization and landscape of functional genes within spatial transcriptomics data.

bioinformatics↗

bioRxiv2023

Shortcut barcoding and early pooling for scalable multiplex single-cell reduced-representation CpG methylation sequencing at single nucleotide resolution

DNA methylation is essential for a wide variety of biological processes, yet the development of a highly efficient and robust technology remains a challenge for routine single-cell analysis. We developed a multiplex scalable single-cell reduced representation bisulfite sequencing (msRRBS) technology with off-the-shelf reagents and equipment. It allows cell-specific barcoded DNA fragments of individual cells to be pooled before bisulfite conversion, free of enzymatic modification or physical capture of the DNA ends, and achieves unparalleled read mapping rates of 62.51%, covering 59.95% of CpG islands and 71.62% of promoters in K562 cells on average. Its reproducibility is shown in duplicates of bulk cells with near perfect correlation (R=0.97-99). At a low 1 Mb of clean reads, msRRBS provides consistent coverage of CpG islands and promoters, outperforming the conventional methods with orders of magnitude reduction in cost. Here, we use this method to characterize the distinct methylation patterns and cellular heterogeneity of 6 cell lines, and leukemia and hepatocellular carcinoma models. Taking 4 hours of hands-on time, msRRBS offers a unique, highly efficient approach for dissecting methylation heterogeneity in a variety of multicellular systems.

genomics↗

bioRxiv2023

Epoxyeicosatrienoic acids and sEH inhibition prevent cardiac dysfunction in CVB3-induced myocarditis by positively regulating type I interferon signaling

Myocarditis is a challenging inflammatory disease of the heart and better understanding of its etiology is needed to develop specific drug therapies. Epoxyeicosatrienoic acids (EETs), active molecules synthesized by cytochrome P450 enzymes from arachidonic acids and hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), have been attributed anti-inflammatory activity. Here, we investigated whether EETs have immunomodulatory activity and exert protective effects on coxsackie B3 virus (CVB3)-induced myocarditis. Viral infection altered eicosanoid epoxide and diol levels in both patients with myocarditis and, in the murine heart, and correlated with the increased expression and activity of the sEH after CVB3 infection. Administration of a sEH inhibitor prevented CVB3-induced cardiac dysfunction and inflammatory infiltration. Importantly, EET/sEH inhibitor treatment attenuated vial infection/ improved viral resistance by activating type I interferon (IFN) signaling. At the molecular level, EETs enhanced the interaction between glycogen synthase kinase 3{beta} (GSK3{beta}) and TANK-binding kinase 1 (TBK1) to promote IFN-{beta} production. Our findings revealed that EETs and sEH inhibitors prevent the progress of CVB3-induced myocarditis, particularly by promoting viral resistance by increasing IFN production.

immunology↗

bioRxiv2023

Serial Capture Affinity Purification and Integrated Structural Modeling of the H3K4me3 Binding and DNA Damage Related WDR76:SPIN1 Complex

WDR76 is a multifunctional protein involved in many cellular functions. With a diverse and complicated protein interaction network, dissecting the structure and function of specific WDR76 complexes is needed. We previously demonstrated the ability of the Serial Capture Affinity Purification (SCAP) method to isolate specific complexes by introducing two proteins of interest as baits at the same time. Here, we applied SCAP to dissect a subpopulation of WDR76 in complex with SPIN1, a histone marker reader that specifically recognizes trimethylated histone H3 lysine4 (H3K4me3). In contrast to the SCAP analysis of the SPIN1:SPINDOC complex, H3K4me3 was copurified with the WDR76:SPIN1 complex. In combination with crosslinking mass spectrometry, we built an integrated structural model of the complex which revealed that SPIN1 recognized the H3K4me3 epigenetic mark while interacting with WDR76. Lastly, interaction network analysis of copurifying proteins revealed the potential role of the WDR76:SPIN1 complex in the DNA damage response. TeaserIn contrast to the SPINDOC/SPIN1 complex, analyses reveal that the WDR76/SPIN1 complex interacts with core histones and is involved in DNA damage.

biochemistry↗

bioRxiv2023

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2. Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

genomics↗

bioRxiv2022

An oral vaccine for SARS-CoV-2 RBD mRNA-bovine milk-derived exosomes induces a neutralizing antibody response in vivo

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) that causes the coronavirus disease 2019 (COVID-19) has presented numerous challenges to global health. The vaccines, including lipid-based nanoparticle mRNA, inactivated virus and recombined protein, have been used to prevent SARS-CoV-2 infections in clinics and are immensely helpful against the epidemic. Here, we first present an oral mRNA vaccine based on bovine milk-derived exosomes (milk-exos), which encodes the SARS-CoV-2 receptor binding domain (RBD) as an immunogen. The results indicated that RBD mRNA delivered by milk-derived exosomes can produce secreted RBD peptide in 293 cells in vitro and stimulated neutralizing antibodies against RBD in mice. These results indicated that bovine milk-derived exosome-based mRNA vaccine could serve as a new strategy for preventing SARS-CoV-2 infection. Meanwhile, it also can work as a new oral delivery system for mRNA. One Sentence SummaryOral SARS-CoV-2 mRNA vaccine based on bovine milk-derived exosomes can stimulate neutralizing antibodies in mice.

immunology↗

bioRxiv2022

A Deep Learning Approach for Histology-Based Nuclei Segmentation and Tumor Microenvironment Characterization

Microscopic examination of pathology slides is essential to disease diagnosis and biomedical research; however, traditional manual examination of tissue slides is laborious and subjective. Tumor whole-slide image (WSI) scanning is becoming part of routine clinical procedure and produces massive data that capture tumor histological details at high resolution. Furthermore, the rapid development of deep learning algorithms has significantly increased the efficiency and accuracy of pathology image analysis. In light of this progress, digital pathology is fast becoming a powerful tool to assist pathologists. Studying tumor tissue and its surrounding microenvironment provides critical insight into tumor initiation, progression, metastasis, and potential therapeutic targets. Nuclei segmentation and classification are critical to pathology image analysis, especially in characterizing and quantifying the tumor microenvironment (TME). Computational algorithms have been developed for nuclei segmentation and TME quantification within image patches; however, existing algorithms are computationally intensive and time-consuming for WSI analysis. In this study, we present Histology-based Detection using Yolo (HD-Yolo), a new method that significantly accelerates nuclei segmentation and TME quantification. We demonstrate that HD-Yolo outperforms existing methods for WSI analysis in nuclei detection and classification accuracy, as well as computation time.

pathology↗

bioRxiv2022

FMRP phosphorylation modulates neuronal translation through YTHDF1

Translation activation of local synaptic mRNAs is critical to learning and memory1-3. Despite extensive studies on how phosphorylation of ribosomal proteins and translation factors enables timely response to exogenous stimuli4, our knowledge on molecular pathways utilized by RNA binding proteins (RBPs) to control translation of specific mRNAs remains incomplete. We have previously found that YTHDF1 regulates depolarization-induced protein synthesis by promoting translation of N6-methyladenosine (m6A)-modified transcripts5. Here we report an unexpected mechanism that the stimuli-induced neuronal translation is mediated by phosphorylation of a YTHDF1-binding protein FMRP. Phosphorylation of FMRP serine 499 induced by neuronal depolarization alters the condensing behavior of prion-like protein YTHDF1. Unphosphorylated FMRP sequesters YTHDF1 away from the translation initiation complex, whereas the stimulation-induced FMRP phosphorylation releases YTHDF1 to form translational active condensates with the ribosome to activate translation of YTHDF1 target transcripts. In fragile X syndrome (FXS) models characterized by low FMRP expression, we observed YTHDF1-mediated hyperactive translation, which notably impacts FXS pathophysiology. Developmental defects in an FXS forebrain organoid model could be reversed by a selective small-molecule inhibitor of YTHDF1 which acts by suppressing its condensation in neurons. We characterized transcriptome-wide mRNA translation with inhibitor treatment in organoids and identified targets that explain alleviated FXS pathology. Our study thus reveals FMRP and its phosphorylation as an important regulator of the activity-dependent translation during neuronal development and stimulation, and identifies YTHDF1 as a potential therapeutic target for FXS in which developmental defects caused by FMRP depletion could be reversed through YTHDF1 inhibition.

molecular biology↗

bioRxiv2022

Styxl2 regulates de novo sarcomere assembly by binding to non-muscle myosin IIs and promoting their degradation

Styxl2, a poorly characterized pseudophosphatase, was identified as a transcriptional target of the Jak1-Stat1 pathway during myoblast differentiation in culture. Styxl2 is specifically expressed in vertebrate striated muscles. By gene knockdown or genetic knockout, we found that Styxl2 plays an essential role in maintaining sarcomere integrity in developing muscles of both zebrafish and mice. To further reveal the functions of Styxl2 in adult muscles, we generated two inducible knockout mouse models: one with Styxl2 being deleted in mature myofibers to assess its role in sarcomere maintenance, and the other in adult muscle satellite cells (MuSCs) to assess its role in de novo sarcomere assembly. We find that Styxl2 is not required for sarcomere maintenance but functions in de novo sarcomere assembly during injury-induced muscle regeneration. Mechanistically, Styxl2 interacts with non-muscle myosin IIs, enhances their ubiquitination, and targets them for autophagy-dependent degradation. Without Styxl2, the degradation of non-muscle myosin IIs is delayed, which leads to defective sarcomere assembly and force generation. Thus, Styxl2 promotes de novo sarcomere assembly by interacting with non-muscle myosin IIs and facilitating their autophagic degradation.

developmental biology↗

bioRxiv2022

The Respiratory Syncytial Virus G Protein Enhances the Immune Responses to the RSV F Protein in an Enveloped Virus-like Particle Vaccine Candidate

Respiratory syncytial virus (RSV) is a serious human respiratory pathogen, but no RSV vaccine has been licensed. Many of the vaccine candidates are focused on the viral F protein. However, it is the G protein that binds the likely receptor, CX3CR1, in human alveolar lung cells raising the question of the importance of the G protein in vaccine candidates. Using virus-like particle (VLP) vaccine candidates, we have directly compared VLPs containing only the pre-fusion F protein, only the G protein, or both glycoproteins. We report that VLPs containing both glycoproteins bind to anti-F protein specific monoclonal antibodies differently than VLPs containing only the pre-fusion F protein. Using RSV naive cotton rats as an animal model, we have found that VLPs assembled only with the pre-F protein stimulated extremely weak neutralizing antibody (NAb) titers as did VLPs assembled with G protein. However, VLPs assembled with both glycoproteins stimulated quite robust neutralizing antibody titers, titers that were significantly higher than the combined titers induced by pre-F only or G only VLPs. VLPs assembled with both glycoproteins induced improved protection of the animals from RSV challenge compared to pre-F VLPs and induced significantly higher levels of antibodies specific for F protein antigenic sites 0, site III, and AM14 binding site compared with VLPs containing only the pre-F protein. These combined results indicate that assembly of pre-F protein with G protein in VLPs further stabilized the pre-fusion conformation or otherwise altered the conformation of the F protein increasing the induction of protective antibodies. ImportanceRSV causes significant disease in infants, young children, and the elderly. Thus, development of an effective vaccine for these populations is a priority. Most ongoing efforts in RSV vaccine development have focused on the viral fusion (F) protein, however, the importance of inclusion of G in vaccine candidates is unclear. Here, using VLPs assembled with only the F protein or only the G protein or both glycoproteins, we show that VLPs assembled with both glycoproteins are a far superior vaccine, in a cotton rat model, than VLPs containing only F protein or only G protein. The results show that the presence of G protein in the VLPs influences the conformation of the F protein and the immune responses to F protein resulting in significantly higher neutralizing antibody titers and better protection from RSV challenge. These results suggest that inclusion of G protein in a vaccine candidate may improve its effectiveness.

microbiology↗

bioRxiv2022

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. Different VQ lines display distinct disease phenotypes and survivals, suggesting significant intra-model variation. Here, we use whole exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify VQ lines into corresponding clusters: Cluster I VQ cells carried recurrent amplification of chromosome (chr) 3 and displayed upregulation of growth pathways and high-risk myeloma gene signatures, whereas Cluster II cells had monosomy chr5 and overexpressed genes and pathways associated with positive response to bortezomib (Btz) treatment in human MM patients. Consistently, in sharp contrast to Cluster II VQ cells that showed short-term response to Btz, Cluster I VQ cells were de novo resistant to Btz in vivo. Our study highlights Cluster I VQ lines as highly representative of human high-risk MM subset.

cancer biology↗

bioRxiv2022

Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. One-Sentence SummaryA oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.

microbiology↗

bioRxiv2022

Alterations in protein kinase networks in astrocytes and neurons derived from patients with familial Alzheimers Disease

Neurons and astrocytes derived from Alzheimers Disease (AD) patient induced pluripotent stem cells are an evolving technology used to study the pathogenesis and etiology of AD. As the utility of mouse models of AD are increasingly coming into questions, using iPSC technology may offer an opportunity to study this disease with human substrates. Herein, we using a hypothesis generating platform, the PamGene12 Kinome Array, to identify core protein kinases in neurons and astrocytes derived from familial AD patient iPSCs. We identified five core protein kinases in these cells and examined the pathways in which they are enriched. Importantly, we complement our findings using an in-silico approach with postmortem AD brain datasets. While these protein kinases have been conceptualized in the context of traditional AD pathology, they have not been explored in the context of aberrant signaling in the pathophysiology of the disease.

neuroscience↗