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Expression Of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling In An Induced Pluripotent Stem Cell Model Of Systemic Amyloid Disease

ABSTRACT: Expression Of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling In An Induced Pluripotent Stem Cell Model Of Systemic Amyloid Disease

PROVIDER: PRJNA643156 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	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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Expression Of Amyloidogenic Transthyretin Drives Hepatic Proteostasis Remodeling In An Induced Pluripotent Stem Cell Model Of Systemic Amyloid Disease

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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Transthyretin alters cardiac fibroblast structure, function and inflammatory gene expression.

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: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.

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Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

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A novel model of Amyloid-beta pathology in C. elegans reveals critically vulnerable neurons as seeds of pathogenicity

Project description:A novel model of amyloid-beta pathology in C. elegans has been generated which allows for substoichiometric fluorescent labeling of amyloid-beta species in living nematodes. By microscopy, FLIM, physiological and biochemical studies, the progress of neurodegeneration and general pathogenicity of amyloidogenic peptides is confirmed. Notably, a single set of neurons was shown to be most vulnerable to Amyloid-beta overexpression and putatively act as a seed for systemic pathogeny. A neuronal version of the amyloid-beta reporter strain was used to perform proteomics analysis from worm lysates after enrichment by immunoprecipitation, using anti-amyloid-beta antibodies.

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A novel model of Amyloid-beta pathology in C. elegans reveals critically vulnerable neurons as seeds of pathogenicity

Project description:A novel model of amyloid-beta pathology in C. elegans has been generated which allows for substoichiometric fluorescent labeling of amyloid-beta species in living nematodes. By microscopy, FLIM, physiological and biochemical studies, the progress of neurodegeneration and general pathogenicity of amyloidogenic peptides is confirmed. Notably, a single set of neurons was shown to be most vulnerable to Amyloid-beta overexpression and putatively act as a seed for systemic pathogeny. A muscular version of the amyloid-beta reporter strain was used to perform proteomics analysis from worm lysates after enrichment by immunoprecipitation, using anti-amyloid-beta antibodies.

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Systemic embolism in amyloid transthyretin cardiomyopathy.

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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