ArticleEMBO molecular medicine2015
A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis.
Article in EMBO molecular medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
97 citing papers in PubMed, 160 citations in OpenAlex.
- Dual pathology in aortic stenosis: Identifying transthyretin amyloidosis likelihood in patients referred for transcatheter aortic valve implantation.International journal of cardiology. Heart & vasculature · 2026Article
- Cryo-EM structures of biopsy-derived TTR fibrils in hereditary transthyretin amyloidosis.Nature communications · 2026Article
- From Hummingbird to Elephant: Amyloid Formation in Natural Transthyretin Variants.bioRxiv : the preprint server for biology · 2026Article
- Transthyretin Amyloidosis-From Peculiar Neuropathy to a Treatable Chronic Multisystemic Disease.Genes · 2026Review
- Induced Circular Dichroism From the Binding of Achiral Bivalent Ligands to Transthyretin.Journal of molecular recognition : JMR · 2026Article
- Cardiac phenotype in hereditary transthyretin amyloidosis: correlations between fibril types and 99mTc-DPD uptake.Scientific reports · 2026Article
- Targeting transthyretin by one Cas9 variant with superfidelity and broad compatibility.Science advances · 2026Article
- Biomolecular mechanisms of cardiac amyloidosis and its cardiovascular pathological basis.Frontiers in immunology · 2026Review
- Navigating the emerging landscape of asymptomatic ATTR-CM: challenges, opportunities and the path ahead.Future cardiology · 2025Review
- In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential.Cardiovascular research · 2025Review
- Integrative structural profiling and ligand optimisation across the transthyretin mutational landscape.NPJ systems biology and applications · 2025Article
- Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis.Journal of medicinal chemistry · 2025Article
- Article
- A Tale of Two Diseases: Decoding Aortic Stenosis and Cardiac Amyloidosis.Journal of clinical medicine · 2025Review
- Broken but not beaten: Challenge of reducing the amyloids pathogenicity by degradation.Journal of advanced research · 2025Review
- Initiation of transthyretin aggregation at neutral pH by fluid agitation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Knowledge Landscape and Hotspots of Research in Transthyretin Amyloid Cardiomyopathy: A Bibliometric Analysis.International journal of medical sciences · 2025Article
- RV-PA uncoupling is associated with increased mortality in transthyretin amyloid cardiomyopathy treated with tafamidis.Clinical research in cardiology : official journal of the German Cardiac Society · 2024Article
- Aggregation of Transthyretin by Fluid Agitation.bioRxiv : the preprint server for biology · 2024Article
- Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology.Current issues in molecular biology · 2024Review
37 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
18 authors at 5 institutions in 3 countries.
Funding
Abstract
The mechanisms underlying transthyretin-related amyloidosis in vivo remain unclear. The abundance of the 49-127 transthyretin fragment in ex vivo deposits suggests that a proteolytic cleavage has a crucial role in destabilizing the tetramer and releasing the highly amyloidogenic 49-127 truncated protomer. Here, we investigate the mechanism of cleavage and release of the 49-127 fragment from the prototypic S52P variant, and we show that the proteolysis/fibrillogenesis pathway is common to several amyloidogenic variants of transthyretin and requires the action of biomechanical forces provided by the shear stress of physiological fluid flow. Crucially, the non-amyloidogenic and protective T119M variant is neither cleaved nor generates fibrils under these conditions. We propose that a mechano-enzymatic mechanism mediates transthyretin amyloid fibrillogenesis in vivo. This may be particularly important in the heart where shear stress is greatest; indeed, the 49-127 transthyretin fragment is particularly abundant in cardiac amyloid. Finally, we show that existing transthyretin stabilizers, including tafamidis, inhibit proteolysis-mediated transthyretin fibrillogenesis with different efficiency in different variants; however, inhibition is complete only when both binding sites are occupied.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.