Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy

Background: Transthyretin cardiomyopathy (TTR-CM) is a progressive, fatal disease caused by the accumulation of misfolded transthyretin (TTR) amyloid fibrils in the heart. Tafamidis is a kinetic stabilizer of TTR that inhibits misfolding and amyloid formation. Methods: In this post hoc analysis, data from an observational study (Transthyretin Amyloidosis Cardiac Study; n = 29) were compared with an open-label study of tafamidis in patients with TTR-CM (Fx1B-201; n = 35). To ensure comparable baseline disease severity, patients with New York Heart Association (NYHA) functional classification ≥III were excluded in this time-to-mortality analysis. Results: Patients with either wild-type or Val122Ile genotypes treated with tafamidis have a significantly longer time to death compared with untreated patients ( P = .0004). Similar results were obtained when limiting the analysis to wild-type patients only, without restricting NYHA functional classification ( P = .0262). Conclusions: These results support earlier conclusions suggesting that tafamidis slows disease progression compared with no treatment outside of standard of care and warrant further investigation. Trial Registration: ClinicalTrials.gov, NCT00694161.

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Synaptic vesicle mimics affect the aggregation of wild-type and A53T α-synuclein variants differently albeit similar membrane affinity

Protein Engineering Design and Selection ◽

10.1093/protein/gzz021 ◽

2019 ◽

Vol 32 (2) ◽

pp. 59-66

Author(s):

Sandra Rocha ◽

Ranjeet Kumar ◽

Istvan Horvath ◽

Pernilla Wittung-Stafshede

Keyword(s):

Synaptic Vesicles ◽

Amyloid Fibrils ◽

Membrane Surface ◽

Amyloid Formation ◽

Wild Type ◽

Membrane Affinity ◽

Axis Parallel ◽

Biophysical Techniques ◽

Small Unilamellar Vesicles ◽

The Brain

Abstract α-Synuclein misfolding results in the accumulation of amyloid fibrils in Parkinson’s disease. Missense protein mutations (e.g. A53T) have been linked to early onset disease. Although α-synuclein interacts with synaptic vesicles in the brain, it is not clear what role they play in the protein aggregation process. Here, we compare the effect of small unilamellar vesicles (lipid composition similar to synaptic vesicles) on wild-type (WT) and A53T α-synuclein aggregation. Using biophysical techniques, we reveal that binding affinity to the vesicles is similar for the two proteins, and both interact with the helix long axis parallel to the membrane surface. Still, the vesicles affect the aggregation of the variants differently: effects on secondary processes such as fragmentation dominate for WT, whereas for A53T, fibril elongation is mostly affected. We speculate that vesicle interactions with aggregate intermediate species, in addition to monomer binding, vary between WT and A53T, resulting in different consequences for amyloid formation.

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The Tenosynovitis of Fingers Associated with Transthyretin Amyloidosis

The Journal of Hand Surgery (Asian-Pacific Volume) ◽

10.1142/s2424835520500381 ◽

2020 ◽

Vol 25 (03) ◽

pp. 340-344

Author(s):

Yukinori Hara ◽

Yasuhito Tajiri ◽

Kenichi Kawano ◽

Shinya Hoshikawa ◽

Yusuke Kita

Keyword(s):

Early Stage ◽

Patient Characteristics ◽

Tendon Sheath ◽

Clinical Findings ◽

Amyloid Deposition ◽

Wild Type ◽

Transthyretin Amyloidosis ◽

Flexor Tendon Sheath ◽

Tunnel Syndrome ◽

The Mean

Background: Amyloidosis treatment has advanced rapidly along with the discovery of drugs to prevent amyloid deposition. Therefore, it is vital to detect amyloidosis at an early stage. Wild-type transthyretin, which can cause carpal tunnel syndrome, may also cause finger tenosynovitis. However, the correlation between wild-type transthyretin amyloid and finger tenosynovitis is unclear. Here, we investigated pathological and clinical findings for 20 patients with finger tenosynovitis who underwent operation at our hospital to determine the frequency of transthyretin amyloid deposition in idiopathic finger tenosynovitis. Methods: To check for the presence of amyloid deposition, all specimens (tendon synovium tissue or flexor tendon sheath) resected during the operation were stained by the direct fast scarlet method. Amyloid-positive specimens were evaluated by immunohistochemical staining using an anti-transthyretin antibody. Patient characteristics were evaluated with respect to amyloid presence. Results: Thirteen (65%) of 20 finger tenosynovitis cases had amyloid deposition. Nine (69.2%) of the 13 amyloid-positive cases exhibited extensive transthyretin staining and were considered to have transthyretin amyloid. Amyloid deposition was more frequent in men. The mean number of fingers with tenosynovitis was significantly higher in amyloid-positive cases (3.8 fingers) than in amyloid-negative cases (2.0 fingers). Conclusions: Men with multiple finger tenosynovitis tended to have transthyretin amyloid deposition. Our results support that multiple finger tenosynovitis may serve as an initial indication of evaluation for transthyretin amyloidosis.

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Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Biomedicines ◽

10.3390/biomedicines7010011 ◽

2019 ◽

Vol 7 (1) ◽

pp. 11 ◽

Cited By ~ 17

Author(s):

Haruki Koike ◽

Masahisa Katsuno

Keyword(s):

Elderly Population ◽

Amyloid Fibrils ◽

Age Of Onset ◽

Therapeutic Option ◽

The Elderly ◽

Organ Damage ◽

Phase Iii ◽

Wild Type ◽

Electron Microscopic ◽

Transthyretin Amyloidosis

Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.

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Sensing and modulation of amyloid fibrils by photo-switchable organic dots

Nanoscale ◽

10.1039/d0nr04312e ◽

2020 ◽

Vol 12 (32) ◽

pp. 16805-16818

Author(s):

Aslam Uddin ◽

Bibhisan Roy ◽

Gregor P. Jose ◽

Sk Saddam Hossain ◽

Partha Hazra

Keyword(s):

Amyloid Fibrils ◽

Amyloid Fibril ◽

Early Stage ◽

Fibril Formation ◽

Amyloid Formation ◽

Amyloid Fibril Formation

Our study demonstrates that organic dots can be used for the imaging and early stage detection of amyloid fibril formation and the modulation of amyloid formation pathways.

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Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1805131115 ◽

2018 ◽

Vol 115 (29) ◽

pp. E6741-E6750 ◽

Cited By ~ 21

Author(s):

Lorena Saelices ◽

Kevin Chung ◽

Ji H. Lee ◽

Whitaker Cohn ◽

Julian P. Whitelegge ◽

...

Keyword(s):

Amyloid Fibrils ◽

Ex Vivo ◽

Standard Of Care ◽

Wild Type ◽

Current Standard ◽

Transthyretin Amyloidosis ◽

Physiological Conditions ◽

Type Gene ◽

Amyloid Diseases

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutantTTRgene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.

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Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.592644 ◽

2020 ◽

Vol 13 ◽

Author(s):

Filipa Bezerra ◽

Maria João Saraiva ◽

Maria Rosário Almeida

Keyword(s):

Amyloid Fibrils ◽

Single Point ◽

Point Mutations ◽

Disease Process ◽

Wild Type ◽

Transthyretin Amyloidosis ◽

Natural Ligand ◽

Single Point Mutations ◽

Pharmacologic Agents ◽

Plasma Stabilization

Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

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Plasmin activity promotes amyloid deposition in a transgenic model of human transthyretin amyloidosis

Nature Communications ◽

10.1038/s41467-021-27416-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ivana Slamova ◽

Rozita Adib ◽

Stephan Ellmerich ◽

Michal R. Golos ◽

Janet A. Gilbertson ◽

...

Keyword(s):

Amyloid Fibrils ◽

Amyloid Deposition ◽

Amyloid Formation ◽

Plasmin Activity ◽

Transthyretin Amyloidosis ◽

In Vivo Models ◽

Transgenic Expression ◽

Attr Amyloidosis ◽

Amyloid Deposits

AbstractCardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTRS52P. The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α2-antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments.

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RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif

Cell Death and Differentiation ◽

10.1038/s41418-020-0598-9 ◽

2020 ◽

Vol 28 (1) ◽

pp. 251-266 ◽

Cited By ~ 1

Author(s):

Hong Hu ◽

Xialian Wu ◽

Guoxiang Wu ◽

Ning Nan ◽

Jing Zhang ◽

...

Keyword(s):

Amyloid Fibrils ◽

Amyloid Formation ◽

Wild Type ◽

Interacting Protein ◽

Kinase Activation ◽

Force Microscopy ◽

Filament Assembly ◽

Atomic Force ◽

Homotypic Interaction ◽

Mutual Antagonism

AbstractNecroptosis is mediated by signaling complexes called necrosomes, which contain receptor-interacting protein 3 (RIP3) and upstream effectors, such as RIP1. In necrosomes, the RIP homotypic interaction motif (RHIM) of RIP3 and RIP1 forms amyloidal complex. But how the amyloidal necrosomes control RIP3 activation and cell necroptosis has not been determined. Here, we showed that RIP3 amyloid fibrils could further assemble into large fibrillar networks which presents as cellular puncta during necroptosis. A viral RHIM-containing necroptosis inhibitor M45 could form heteroamyloid with RIP3 in cells and prevent RIP3 puncta formation and cell necroptosis. We characterized mutual antagonism between RIP3–RHIM and M45–RHIM in necroptosis regulation, which was caused by distinct inter-filament interactions in RIP3, M45 amyloids revealed with atomic force microscopy. Moreover, double mutations Asn464 and Met468 in RIP3–RHIM to Asp disrupted RIP3 kinase-dependent necroptosis. While the mutant RIP3(N464D/M468D) could form amyloid as wild type upon necroptosis induction. Based on these results, we propose that RIP3 amyloid formation is required but not sufficient in necroptosis signaling, the ordered inter-filament assembly of RIP3 is critical in RIP3 amyloid mediated kinase activation and cell necroptosis.

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Diagnostic algorithm in transthyretin amyloidosis with cardiomyopathy

Bulgarian Cardiology ◽

10.3897/bgcardio.26.e53407 ◽

2020 ◽

Vol 26 (2) ◽

pp. 5-20

Author(s):

Mariana Gospodinova ◽

Elena Kinova ◽

Iana Simova ◽

Yoto Yotov ◽

Marina Garcheva ◽

...

Keyword(s):

Amyloid Fibrils ◽

Early Recognition ◽

Multimodality Imaging ◽

Diagnostic Algorithm ◽

Restrictive Cardiomyopathy ◽

Wild Type ◽

Transthyretin Amyloidosis ◽

Life Threatening ◽

Timely Treatment ◽

Centres Of Expertise

Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy ((ATTR-CM), caused by an extracellular deposition of insoluble amyloid fibrils in the myocardium. It is a life threatening disease with life expectancy of 2 to 6 years after diagnosis. There are two types – hereditary and wild type. Recent data reveal that the wild type ATTR-CM is a common cause of heart failure with preserved ejection fraction, especially in elderly men. Hereditary ATTR amyloidosis is not so rare in Bulgaria. Five different mutations have been diagnosed, the most common being p.Glu89Gln, identified in 62 unrelated families with 117 patients and 72 mutation carriers. ATTR-CM diagnosis is often delayed or even missed, however its early recognition has become very important as a new drug, which is a transthyretin stabilizer is now available and other drugs are under development. Updated knowledge about the clinical presentation, diagnostic algorithm, available and future therapeutic options for ATTR-CM are a prerequisite for an early identification, timely treatment and better prognosis of the affected patients. The diagnosis requires a multidisciplinary approach with the participation of experienced specialists, multimodality imaging, well equipped histopathological and genetic laboratories. Establishing centres of expertise could improve the management of the patients with ATTR-CM.

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Apomorphine Targets the Pleiotropic Bacterial Regulator Hfq

Antibiotics ◽

10.3390/antibiotics10030257 ◽

2021 ◽

Vol 10 (3) ◽

pp. 257

Author(s):

Florian Turbant ◽

David Partouche ◽

Omar El Hamoui ◽

Sylvain Trépout ◽

Théa Legoubey ◽

...

Keyword(s):

Small Rnas ◽

Antibacterial Agents ◽

Amyloid Fibrils ◽

Noncoding Rnas ◽

Amyloid Formation ◽

Gram Negative Bacteria ◽

Translation Efficiency ◽

Gram Negative ◽

Bacterial Adaptation ◽

E Coli

Hfq is a bacterial regulator with key roles in gene expression. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, thanks to its binding to small regulatory noncoding RNAs. This property is of primary importance for bacterial adaptation and survival in hosts. Small RNAs and Hfq are, for instance, involved in the response to antibiotics. Previous work has shown that the E. coli Hfq C-terminal region (Hfq-CTR) self-assembles into an amyloid structure. It was also demonstrated that the green tea compound EpiGallo Catechin Gallate (EGCG) binds to Hfq-CTR amyloid fibrils and remodels them into nonamyloid structures. Thus, compounds that target the amyloid region of Hfq may be used as antibacterial agents. Here, we show that another compound that inhibits amyloid formation, apomorphine, may also serve as a new antibacterial. Our results provide an alternative in order to repurpose apomorphine, commonly used in the treatment of Parkinson’s disease, as an antibiotic to block bacterial adaptation to treat infections.

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