scholarly journals Synaptotagmin-7 deficiency induces mania-like behavioral abnormalities through attenuating GluN2B activity

2020 ◽  
Vol 117 (49) ◽  
pp. 31438-31447
Author(s):  
Qiu-Wen Wang ◽  
Si-Yao Lu ◽  
Yao-Nan Liu ◽  
Yun Chen ◽  
Hui Wei ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Bipolar Depression ◽  
Glutamate Release ◽  
Induced Pluripotent Stem Cell ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Behavioral Abnormalities ◽  
Synaptic Region ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Synaptotagmin-7 (Syt7) probably plays an important role in bipolar-like behavioral abnormalities in mice; however, the underlying mechanisms for this have remained elusive. Unlike antidepressants that cause mood overcorrection in bipolar depression,N-methyl-d-aspartate receptor (NMDAR)-targeted drugs show moderate clinical efficacy, for unexplained reasons. Here we identified Syt7 single nucleotide polymorphisms (SNPs) in patients with bipolar disorder and demonstrated that mice lacking Syt7 or expressing the SNPs showed GluN2B-NMDAR dysfunction, leading to antidepressant behavioral consequences and avoidance of overcorrection by NMDAR antagonists. In human induced pluripotent stem cell (iPSC)-derived and mouse hippocampal neurons, Syt7 and GluN2B-NMDARs were localized to the peripheral synaptic region, and Syt7 triggered multiple forms of glutamate release to efficiently activate the juxtaposed GluN2B-NMDARs. Thus, while Syt7 deficiency and SNPs induced GluN2B-NMDAR dysfunction in mice, patient iPSC-derived neurons showed Syt7 deficit-induced GluN2B-NMDAR hypoactivity that was rescued by Syt7 overexpression. Therefore, Syt7 deficits induced mania-like behaviors in mice by attenuating GluN2B activity, which enabled NMDAR antagonists to avoid mood overcorrection.

scholarly journals Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

2021 ◽  
Author(s):  
Tara E Tracy ◽  
Jesus Madero-Perez ◽  
Danielle Swaney ◽  
Timothy S Chang ◽  
Michelle Moritz ◽  
...  
Keyword(s):  
Affinity Purification ◽  
Induced Pluripotent Stem Cell ◽  
Proximity Ligation Assay ◽  
Spatiotemporal Resolution ◽  
Proximity Ligation ◽  
Cytosolic Domains ◽  
Presynaptic Vesicle ◽  
Underlying Mechanisms ◽  
Induced Pluripotent ◽  
Affinity Purification Mass Spectrometry

Tau (MAPT) drives neuronal dysfunction in Alzheimer's disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Tau's role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

scholarly journals A Mechanism Leading to Changes in Copy Number Variations Affected by Transcriptional Level Might Be Involved in Evolution, Embryonic Development, Senescence, and Oncogenesis Mediated by Retrotransposons

2021 ◽  
Vol 9 ◽  
Author(s):  
Yunpeng Sui ◽  
Shuanghong Peng
Keyword(s):  
Embryonic Development ◽  
Copy Number ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Copy Number Variations ◽  
Mrna Splicing ◽  
Transcriptional Level ◽  
Underlying Mechanisms ◽  
Induced Pluripotent ◽  
Hiv 1

In recent years, more and more evidence has emerged showing that changes in copy number variations (CNVs) correlated with the transcriptional level can be found during evolution, embryonic development, and oncogenesis. However, the underlying mechanisms remain largely unknown. The success of the induced pluripotent stem cell suggests that genome changes could bring about transformations in protein expression and cell status; conversely, genome alterations generated during embryonic development and senescence might also be the result of genome changes. With rapid developments in science and technology, evidence of changes in the genome affected by transcriptional level has gradually been revealed, and a rational and concrete explanation is needed. Given the preference of the HIV-1 genome to insert into transposons of genes with high transcriptional levels, we propose a mechanism based on retrotransposons facilitated by specific pre-mRNA splicing style and homologous recombination (HR) to explain changes in CNVs in the genome. This mechanism is similar to that of the group II intron that originated much earlier. Under this proposed mechanism, CNVs on genome are dynamically and spontaneously extended in a manner that is positively correlated with transcriptional level or contract as the cell divides during evolution, embryonic development, senescence, and oncogenesis, propelling alterations in them. Besides, this mechanism explains several critical puzzles in these processes. From evidence collected to date, it can be deduced that the message contained in genome is not just three-dimensional but will become four-dimensional, carrying more genetic information.

Coagulopathy in Type 2 Diabetes Mellitus: Pathological Mechanisms and the Role of Factor XIII-A Single Nucleotide Polymorphisms

2019 ◽  
Vol 15 (6) ◽  
pp. 446-455
Author(s):  
Marry-ann Ntanyane Phasha ◽  
Prashilla Soma ◽  
Etheresia Pretorius ◽  
Alia Phulukdaree
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Single Nucleotide Polymorphisms ◽  
Factor Xiii ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Underlying Mechanisms

The prevalence of type 2 diabetes mellitus (T2DM) has quadrupled within three decades since 1980, affecting 422 million adults in 2016. It remains one of the most common noncommunicable chronic diseases and the underlying risk factor for cardiovascular diseases worldwide. There are different underlying mechanisms that play a role in the development of pathologies associated with the disease such as hyperglycaemia, oxidative stress, obesity, inflammation and hypercoagulation; each of which are interlinked. Hyperglycaemia, oxidative stress and obesity play a huge role in the activation of inflammation and coagulation. Activation of inflammatory pathways increases the production of thrombin which predisposes the development of thrombotic related diseases. One of the factors that contribute to the increase of thrombin is the impairment of the fibrinolysis process due to decreased expression of tissue-plasminogen activator (tPA) by increased levels of plasminogen activator inhibitor-1 (PAI-1). Coagulation factor XIII (FXIII), a transglutaminase that is composed of subunits A and B (FXIII-A2B2), is essential for the last step of fibrin clot formation in the coagulation pathway. Genetic variation of FXIII-A in the form of single nucleotide polymorphisms (SNPs) alters the activity of FXIII, altering clot properties which influence disease outcomes. This review discusses the link between underlying mechanisms of T2DM, well known FXIII-A variants and coagulation.

Abstract 520: Structural, Molecular, and Electrophysiological Maturation of Human Induced Pluripotent Stem Cell Derived Atrial Cardiomyocytes to Serve as a Model for Atrial Fibrillation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Olivia T Ly ◽  
Grace Brown ◽  
Liang HONG ◽  
Arvind Sridhar ◽  
Meihong Zhang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Electrode Array ◽  
Induced Pluripotent Stem Cell ◽  
Rna Seq ◽  
Patch Clamping ◽  
Cellular Mechanisms ◽  
Transmission Electron ◽  
Underlying Mechanisms ◽  
Induced Pluripotent ◽  
Scn5a Mutation

Background: Atrial fibrillation (AF), the most common arrhythmia, is associated with significant morbidity and increased mortality. Although antiarrhythmic drugs are still commonly used to treat symptomatic AF, membrane-active drugs are incompletely and unpredictably effective, failing to target the underlying mechanisms of AF. Our pilot data shows atrial iPSC-CMs generated from a familial AF kindred recapitulated the electrophysiologic (EP) phenotype of an AF-linked SCN5A mutation, serving as a novel platform to target underlying cellular AF mechanisms. However, structural, molecular, and EP immaturity as compared to adult atrial CMs has hindered successful mechanistic evaluation. Objective: We aim to determine optimal condition(s) to enhance the maturity of atrial iPSC-CMs, establishing them as a novel platform to model AF, elucidate the cellular mechanisms, and identify/assess novel, mechanism based therapies. Methods: Maturity of atrial iPSC-CMs was enhanced using TID (T3, IGF-1, dexamethasone), fatty acids (FA), acute electrical stimulation (ES), and extracellular matrix (ECM) modulation. We examined for improvements in structural maturity (immunofluorescence, transmission electron microscopy), molecular (qPCR, RNA seq) and EP (patch clamping, multi-electrode array, high-throughput automated patch clamping). The maturity of atrial iPSC-CMs was compared with adult atrial CMs obtained from the same patient during cardiac surgery. Results and Conclusion: Fig. 1 demonstrates that acute ES, combined with TID and FA supplementation, significantly improves structural and in part EP maturity of atrial iPSC-CMs.

scholarly journals Cell Transplantation for Spinal Cord Injury: Tumorigenicity of Induced Pluripotent Stem Cell-Derived Neural Stem/Progenitor Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Junhao Deng ◽  
Yiling Zhang ◽  
Yong Xie ◽  
Licheng Zhang ◽  
Peifu Tang
Keyword(s):  
Spinal Cord ◽  
Stem Cells ◽  
Spinal Cord Injury ◽  
Embryonic Stem ◽  
Induced Pluripotent Stem Cell ◽  
Therapeutic Effects ◽  
Cord Injury ◽  
Neural Stem Progenitor Cells ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Spinal cord injury (SCI) is an intractable and worldwide difficult medical challenge with limited treatments. Neural stem/progenitor cell (NS/PC) transplantation derived from fetal tissues or embryonic stem cells (ESCs) has demonstrated therapeutic effects via replacement of lost neurons and severed axons and creation of permissive microenvironment to promote repair of spinal cord and axon regeneration but causes ethnical concerns and immunological rejections as well. Thus, the implementation of induced pluripotent stem cells (iPSCs), which can be generated from adult somatic cells and differentiated into NS/PCs, provides an effective alternation in the treatment of SCI. However, as researches further deepen, there is accumulating evidence that the use of iPSC-derived NS/PCs shows mounting concerns of safety, especially the tumorigenicity. This review discusses the tumorigenicity of iPSC-derived NS/PCs focusing on the two different routes of tumorigenicity (teratomas and true tumors) and underlying mechanisms behind them, as well as possible solutions to circumvent them.

scholarly journals Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marion Bonneau ◽  
Shane T. O’ Sullivan ◽  
Miguel A. Gonzalez-Lozano ◽  
Paul Baxter ◽  
Phillippe Gautier ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Large Scale ◽  
Pyramidal Neurons ◽  
Mutant Mouse ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
Translocation Carrier ◽  
Genetic Studies ◽  
Increased Risk ◽  
Induced Pluripotent

AbstractA balanced t(1;11) translocation that directly disrupts DISC1 is linked to schizophrenia and affective disorders. We previously showed that a mutant mouse, named Der1, recapitulates the effect of the translocation upon DISC1 expression. Here, RNAseq analysis of Der1 mouse brain tissue found enrichment for dysregulation of the same genes and molecular pathways as in neuron cultures generated previously from human t(1;11) translocation carriers via the induced pluripotent stem cell route. DISC1 disruption therefore apparently accounts for a substantial proportion of the effects of the t(1;11) translocation. RNAseq and pathway analysis of the mutant mouse predicts multiple Der1-induced alterations converging upon synapse function and plasticity. Synaptosome proteomics confirmed that the Der1 mutation impacts synapse composition, and electrophysiology found reduced AMPA:NMDA ratio in hippocampal neurons, indicating changed excitatory signalling. Moreover, hippocampal parvalbumin-positive interneuron density is increased, suggesting that the Der1 mutation affects inhibitory control of neuronal circuits. These phenotypes predict that neurotransmission is impacted at many levels by DISC1 disruption in human t(1;11) translocation carriers. Notably, genes implicated in schizophrenia, depression and bipolar disorder by large-scale genetic studies are enriched among the Der1-dysregulated genes, just as we previously observed for the t(1;11) translocation carrier-derived neurons. Furthermore, RNAseq analysis predicts that the Der1 mutation primarily targets a subset of cell types, pyramidal neurons and interneurons, previously shown to be vulnerable to the effects of common schizophrenia-associated genetic variants. In conclusion, DISC1 disruption by the t(1;11) translocation may contribute to the psychiatric disorders of translocation carriers through commonly affected pathways and processes in neurotransmission.

scholarly journals KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hui-Yi Lin ◽  
◽  
Po-Yu Huang ◽  
Chia-Ho Cheng ◽  
Heng-Yuan Tung ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Gene Interactions ◽  
Polygenic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Biological Functions ◽  
Single Nucleotide ◽  
Protein Protein Interaction ◽  
Cancer Aggressiveness ◽  
Underlying Mechanisms ◽  
Snp Interaction

AbstractRisk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP–SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10–9) and 3145 (P < 1 × 10–5) SNP–SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene–gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP–SNP interactions were supported by gene expression and protein–protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

scholarly journals Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids

2020 ◽  
Author(s):  
Soraia Martins ◽  
Lars Erichsen ◽  
Angeliki Datsi ◽  
Wasco Wruck ◽  
Wolfgang Goering ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Genetic Disorder ◽  
Clinical Manifestations ◽  
Induced Pluripotent Stem Cell ◽  
Nijmegen Breakage Syndrome ◽  
Damage Repair ◽  
Damage Response ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive genetic disorder caused by mutations within NBN, a DNA-damage repair protein. Hallmarks of NBS include several clinical manifestations such growth retardation, chromosomal instability, immunodeficiency and progressive microcephaly. However, the etiology of microcephaly in NBS patients remains elusive. Here, we employed induced pluripotent stem cell-derived brain organoids from two NBS patients to analyze the underlying mechanisms of microcephaly. We show that NBS-organoids carrying the homozygous 647del5 NBN mutation are significantly smaller in size with disrupted cyto-architecture Patient-derived organoids exhibit premature differentiation together with neuronatin (NNAT) overexpression and key pathways related to DNA damage response and cell cycle are differentially regulated compared to controls. Moreover, we show that after exposure to bleomycin, NBS organoids undergo a delayed p53-mediated DNA damage response and aberrant trans-synaptic signalling, which ultimately leads to neuronal apoptosis. Our data provide insights into how mutations within NBN alters neurogenesis in NBS patients, thus providing a proof of concept that cerebral organoids are a valuable tool for studying DNA damage-related disorders.

scholarly journals Mechanisms and Insights for the Development of Heart Failure Associated with Cancer Therapy

Children ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 829
Author(s):  
Claire Fraley ◽  
Sarah A. Milgrom ◽  
Lavanya Kondapalli ◽  
Matthew R. G. Taylor ◽  
Luisa Mestroni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Induced Pluripotent Stem Cell ◽  
Childhood Cancer Survivors ◽  
Cardiovascular Complications ◽  
Cancer Therapies ◽  
Hematopoietic Stem ◽  
Targeted Cancer Therapies ◽  
Underlying Mechanisms ◽  
Induced Pluripotent

Cardiotoxicity is a well-recognized late effect among childhood cancer survivors. With various pediatric cancers becoming increasingly curable, it is imperative to understand the disease burdens that survivors may face in the future. In order to prevent or mitigate cardiovascular complications, we must first understand the mechanistic underpinnings. This review will examine the underlying mechanisms of cardiotoxicity that arise from traditional antineoplastic chemotherapies, radiation therapy, hematopoietic stem cell transplantation, as well as newer cellular therapies and targeted cancer therapies. We will then propose areas for prevention, primarily drawing from the anthracycline-induced cardiotoxicity literature. Finally, we will explore the role of human induced pluripotent stem cell cardiomyocytes and genetics in advancing the field of cardio-oncology.

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