Expression Of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling In An Induced Pluripotent Stem Cell Model Of Systemic Amyloid Disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA643156 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR12117100.fastq.gz | Fastqsanger.gz | |||
| SRR12117200.fastq.gz | Fastqsanger.gz | |||
| SRR12117300.fastq.gz | Fastqsanger.gz | |||
| SRR12117400.fastq.gz | Fastqsanger.gz | |||
| SRR12117500.fastq.gz | Fastqsanger.gz |
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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.
2020-07-01 | GSE153541 | GEO
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 hepatocyte-like cells (HLCs) to the proteotoxicity of secreted transthyretin (TTR). To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We combined this tool with single-cell RNA sequencing to identify hepatic proteostasis factors correlating with destabilized TTR production in iPSC-derived HLCs. By generating an ATF6 inducible patient-specific iPSC line, we demonstrated that enhancing hepatic ER proteostasis preferentially reduces the secretion of amyloidogenic TTR. These data highlight the liver's capacity to chaperone misfolded TTR prior to deposition, and moreover suggest the potential for unfolded protein response modulating therapeutics in the treatment of diverse systemic amyloidoses.
| S-EPMC7419739 | biostudies-literature
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:Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms
| PRJNA647190 | ENA
Project description:AimsAlthough systemic embolism is a potential complication in transthyretin amyloid cardiomyopathy (ATTR-CM), data about its incidence and prevalence are scarce. We studied the incidence, prevalence and factors associated with embolic events in ATTR-CM. Additionally, we evaluated embolic events according to the type of oral anticoagulation (OAC) and the performance of the CHA2 DS2 -VASc score in this setting.Methods and resultsClinical characteristics, history of atrial fibrillation (AF) and embolic events were retrospectively collected from ATTR-CM patients evaluated at four international amyloid centres. Overall, 1191 ATTR-CM patients (87% men, median age 77.1 years [interquartile range-IQR 71.4-82], 83% ATTRwt) were studied. A total of 162 (13.6%) have had an embolic event before initial evaluation. Over a median follow-up of 19.9 months (IQR 9.9-35.5), 41 additional patients (3.44%) had an embolic event. Incidence rate (per 100 patient-years) was 0 among patients in sinus rhythm with OAC, 1.3 in sinus rhythm without OAC, 1.7 in AF with OAC, and 4.8 in AF without OAC. CHA2 DS2 -VASc did not predict embolic events in patients in sinus rhythm whereas in patients with AF without OAC, only those with a score ≥4 had embolic events. There was no difference in the incidence rate of embolism between patients with AF treated with vitamin K antagonists (VKAs) (n = 322) and those treated with direct oral anticoagulants (DOACs) (n = 239) (p = 0.66).ConclusionsEmbolic events were a frequent complication in ATTR-CM. OAC reduced the risk of systemic embolism. Embolic rates did not differ with VKAs and DOACs. The CHA2 DS2 -VASc score did not correlate well with clinical outcome in ATTR-CM and should not be used to assess thromboembolic risk in this population.
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Project description:Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly-selective IRE1 activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
2020-04-17 | GSE148802 | GEO
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.
2021-06-02 | GSE175917 | GEO
Project description:The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other non-cardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator. DNA was extracted from whole blood of Yale-Penn participants using the EZ-96 DNA methylation kit (Zymo Research, CA, USA). DNA methylation was assayed using the Illumina Infinium MethylationEPIC chip quantifying >850,000 CpG sites and imaged on the Illumina iScan system at YCGA. The methylation intensity data (*.idat files) was exported for analysis using the manufacturer's recommended protocol using the GenomeStudio methylation module.
2020-12-31 | GSE154683 | GEO
Project description:Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. 10 symptomatic ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied. Human Schwann cells cultures were used to study the regulatory effects of miR-150-5p on the expression of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). ATTRv patients had 33 miRNAs up-regulated and 48 down-regulated versus healthy controls; 9 miRNAs were up-regulated and 30 down-regulated versus CMT patients; 19 miRNAs were up-regulated and 38 down-regulated versus asymptomatic TTRv carriers. Twelve out of the 19 upregulated miRNAs had a fold increase higher than 100. The validation experiment indicated miR-150-5p as a valuable biomarker to differentiate ATTRv patients from asymptomatic TTRv carriers (AUC: 0.9728; p<0.0001). Schwann cells culture model demonstrated that miR-150-5p is a powerful negative regulator of CREB, BDNF and NGF genes. Identification of deregulated miRNAs can help in understanding the complex pathomechamism underlying the development of ATTRv and related multisystemic pathology. Further investigations are needed on the role of circulating miR-150-5p to predict the shift of TTRv carriers from an asymptomatic status to symptoms appearance.
2020-05-31 | GSE149665 | GEO
Project description:Krohn2011 - Cerebral amyloid-β
proteostasis regulated by membrane transport protein ABCC1
This model is described in the article:
Cerebral amyloid-β
proteostasis is regulated by the membrane transport protein
ABCC1 in mice.
Krohn M, Lange C, Hofrichter J,
Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T,
Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A,
Gsponer J, Walker LC, Pahnke J.
J. Clin. Invest. 2011 Oct; 121(10):
3924-3931
Abstract:
In Alzheimer disease (AD), the intracerebral accumulation of
amyloid-β (Aβ) peptides is a critical yet poorly understood
process. Aβ clearance via the blood-brain barrier is reduced by
approximately 30% in AD patients, but the underlying mechanisms
remain elusive. ABC transporters have been implicated in the
regulation of Aβ levels in the brain. Using a mouse model of AD
in which the animals were further genetically modified to lack
specific ABC transporters, here we have shown that the
transporter ABCC1 has an important role in cerebral Aβ
clearance and accumulation. Deficiency of ABCC1 substantially
increased cerebral Aβ levels without altering the expression of
most enzymes that would favor the production of Aβ from the Aβ
precursor protein. In contrast, activation of ABCC1 using
thiethylperazine (a drug approved by the FDA to relieve nausea
and vomiting) markedly reduced Aβ load in a mouse model of AD
expressing ABCC1 but not in such mice lacking ABCC1. Thus, by
altering the temporal aggregation profile of Aβ,
pharmacological activation of ABC transporters could impede the
neurodegenerative cascade that culminates in the dementia of
AD.
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2024-09-02 | BIOMD0000000618 | BioModels