Expression data from hippocampus in mouse brain
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE179968 | GEO | 2021/07/13
REPOSITORIES: GEO
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Project description:Age-related wild type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton disorganized, focal adhesion formation decreased, and nuclear shape was flattened. Fibroblasts had faster collective and single cell migration velocities on TTR-deposited substrates. Additionally, fibroblasts cultured on microposts with TTR deposition had reduced attachment and increased proliferation above untreated. Transcriptomic and proteomic analyses of fibroblasts grown on glass covered with TTR showed significant upregulation of inflammatory genes after 48 hours, indicative of progression in TTR-based diseases. Together, results suggest that TTR deposited in tissue extracellular matrix may affect both the structure, function and gene expression of cardiac fibroblasts. As therapies for wtATTR are cost-prohibitive and only slow disease progression, better understanding of cellular maladaptation may elucidate novel therapeutic targets.
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Project description:Purpose: Compare the transciptome between lung myofibroblasts that contituatively express Fra-2 to control lung myofibroblasts to determine genes that may contribute to regulation of secondary alveolar septation Methods: mRNa sequences from lung myofibroblasts isolated from mutant mice that contituatively express Fra-2 in α-SMA expressing cells (sma-Fra2) were compared to control mice. n=4 in each group Results: 43,432 transcripts wre analyzed and 361 genes were differentially expressed in the smaFra2 mice compared to wild type control. Functional analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. Changes in genes from lung myofibroblasts in smaFra2 mice: genes involved with extracellular matrix and cell adhesion were upregulated; Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (Enpp2) and LPA receptor1 (LPA1) were downregulated. Coclusion: The secondary alveolar septation defect in smaFra2 mice could be explaned by Fra-2 mediated changes in extracellular matrix and cell adhesion in developing lung myofibroblasts.
2018-01-01 | GSE94857 | GEO
Project description:We have developed a new mouse model of transthyretin (TTR) amyloidosis using transgenic mice expressing the most fibrillogenic variant of TTR (S52P). Following seeding with amyloid fibrils, TTR amyloid is deposited mainly in the heart and tongue. The fibrils contain both full length and truncated (49-127) TTR. The presence of S52P TTR was confirmed by proteomics. Knockout of alpha2-antiplasmin enhanced amyloid deposition.
2021-12-27 | PXD027747 | Pride
Project description:Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Methods and Results: Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.
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Project description:The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well-described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of HLCs to the proteotoxicity of secreted TTR. To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We subsequently differentiated these lines into HLCs and performed single cell RNA sequencing (scRNAseq) via the Fluidigm C1 platform in an effort to identify a destabilized TTR-derived disease signature. Upon doing so, we identified a number of hepatic proteostasis factors (e.g. the unfolded protein response, UPR, as well as known and novel chaperone genes) whose expression correlates with the production destabilized TTR production.
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Project description:Ageing and mutations of transthyretin (TTR), the thyroid hormones and retinol transporting protein lead to amyloidosis by destabilizing the structure of TTR. Because protein structure is regulated through posttranslational modifications, we investigated the Small Ubiquitin-like Modifier (SUMO)ylation of TTR. We chose the widely used Ubc9 fusion-directed SUMOylation system, which is based on a fusion of the SUMOylation substrate of interest with Ubc9, a sole SUMO conjugating enzyme. Surprisingly, despite our presumptions, we found that Ubc9 fused to TTR was SUMOylated at a unique set of lysine residues. Three unknown SUMOylation sites of Ubc9—K154, K18 and K65—were revealed by mass spectrometry (MS). The previously reported SUMOylation at K49 of Ubc9 was also observed. SUMOylation of the lysine residues of TTR fused to Ubc9 was hardly detectable. However, non-fused TTR was SUMOylated via trans-SUMOylation by Ubc9 fused to TTR. Interestingly, mutating the catalytic residue of Ubc9 fused to TTR did not result in complete loss of the SUMOylation signal, suggesting that Ubc9 linked to TTR is directly cross-SUMOylated by the SUMO-activating enzyme E1. Ubc9, TTR or fusion proteins composed of TTR and Ubc9 specifically affected the global SUMOylation of cellular proteins. TTR or Ubc9 alone increased global SUMOylation, whereas TTR and Ubc9 together decreased the amount of high-molecular weight (HMW) SUMO conjugates. Our data suggest that TTR may influence the SUMOylation of Ubc9, thereby altering signalling pathways in the cell.
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Project description:Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder characterized by the extracellular deposition of mutant transthyretin (TTR). The most common TTR mutation in FAP results from an exchange of a methionine for a valine at position 30 â TTR V30M. In an attempt to establish an animal model of TTR Met-30-associated homozygous familial amyloidotic polyneuropathy and to study the structural and functional properties of human TTR Met 30, it was generated a mouse line carrying a null mutation at the endogenous ttr locus (ttr-/-) and the human mutant ttr gene (6.0-hMet 30) as a transgene. For microarray analysis, messenger RNA (mRNA) from WT and V30M injured sciatic nerves was extracted 7 days post-lesion (n=2 per strain), using the Lipid Tissue Mini Kit (Qiagen). mRNA integrity was assessed with Experion RNA StdSens Analysis Kit (Bio-Rad); samples used had a similar RNA quality indicator (RQI). Equal amounts of mRNA extract (200 ng) from each replicate were amplified and Cy-3-labeled using the Low Input Quick Amp Labeling kit (Agilent Technologies). In vitro synthesized transcripts (Spike-in kit), in pre-determinated ratios, were used to monitor microarray workflow for linearity, sensitivity and accuracy. Hybridizations were carried out at 65°C for 17 h, following Agilent manufactureâs instructions for One-Color Microarray-Based Gene Expression Analysis, using Mouse whole-genome 4 à 44K v2 Microarray slides. After washing, microarray slides were immediately scanned in the Agilent G2565AB microarray scanner and fluorescence quantification performed with Agilent Feature Extraction 10.5.1.1 software, following the GE1_105_Dec08 protocol. The signal intensity was aligned by centering the median of the signal distribution using the Biometric Research Branch (BRB)-ArrayTools v3.4.0, taking median array intensity as reference.
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