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Drug Design, Development and Therapy 2020Transthyretin (TTR) is a tetrameric protein, and its dissociation, aggregation, deposition, and misfolding are linked to several human amyloid diseases. As the main... (Review)
Review
Transthyretin (TTR) is a tetrameric protein, and its dissociation, aggregation, deposition, and misfolding are linked to several human amyloid diseases. As the main transporter for thyroxine (T4) in plasma and cerebrospinal fluid, TTR contains two T4-binding sites, which are docked with T4 and subsequently maintain the structural stability of TTR homotetramer. Affected by genetic disorders and detrimental environmental factors, TTR degrades to monomer and/or form amyloid fibrils. Reasonably, stabilization of TTR might be an efficient strategy for the treatment of TTR-related amyloidosis. However, only 10-25% of T4 in the plasma is bound to TTR under physiological conditions. Expectedly, T4 analogs with different structures aiming to bind to T4 pockets may displace the functions of T4. So far, a number of compounds including both natural and synthetic origin have been reported. In this paper, we summarized the potent inhibitors, including bisaryl structure-based compounds, flavonoids, crown ethers, and carboranes, for treating TTR-related amyloid diseases and the combination modes of some compounds binding to TTR protein.
Topics: Amyloid; Amyloidosis; Humans; Models, Molecular; Molecular Structure; Prealbumin
PubMed: 32210536
DOI: 10.2147/DDDT.S237252 -
International Journal of Molecular... May 2019Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown... (Review)
Review
Elevated pro-inflammatory biomarkers and cytokines are associated with morbidity and mortality in heart failure (HF). Preclinical and clinical studies have shown multiple inflammatory mechanisms causing cardiac remodeling, dysfunction and chronic failure. Therapeutics in trials targeting the immune response in heart failure and its effects did not result in evident benefits regarding clinical endpoints and mortality. This review elaborates pathways of immune cytokines in pathogenesis and worsening of heart failure in clinical and cellular settings. Besides the well-known mechanisms of immune activation and inflammation in atherosclerosis causing ischemic cardiomyopathy or myocarditis, attention is focused on other mechanisms leading to heart failure such as transthyretin (TTR) amyloidosis or heart failure with preserved ejection fraction. The knowledge of the pathogenesis in heart failure and amyloidosis on a molecular and cellular level might help to highlight new disease defining biomarkers and to lead the way to new therapeutic targets.
Topics: Amyloidosis; Heart Failure; Humans; Inflammation; Myocardial Ischemia; Prealbumin; Signal Transduction
PubMed: 31083399
DOI: 10.3390/ijms20092322 -
JBRA Assisted Reproduction Jun 2017Familial amyloid polyneuropathy was first described by Corino de Andrade in 1952 in Northern Portugal. It is a fatal autosomal dominant neurodegenerative disorder... (Review)
Review
Familial amyloid polyneuropathy was first described by Corino de Andrade in 1952 in Northern Portugal. It is a fatal autosomal dominant neurodegenerative disorder characterized by a progression of neurologic symptoms, beginning early in the reproductive life. The Transthyretin gene mutation originates a mutated protein that precipitates in the connective tissue as amyloid deposits. This disease is presently named Transthyretin-related hereditary amyloidosis. We performed an extensive review on this disease based on searches in Medical databases and in paper references. In this review, we briefly summarize the epidemiology and the mechanisms involved on amyloid deposition; we detailed how to evaluate the mechanisms implicated on the development of the major signs and symptoms associated with reproductive dysfunction; and we discuss the mechanisms involved in secondary sexual dysfunction after psychological treatments. Treatment of the disease is directed towards relieving specific symptoms in association with liver transplant, and molecular and genetic therapeutics. Although the current clinical trials indicate symptoms relief, no data on the reproductive function was reported. Thus, preimplantation genetic diagnosis is presently the only available technique that eradicates the disease as it avoids the birth of new patients.
Topics: Adult; Amyloid Neuropathies, Familial; Female; Humans; Male; Mutation; Peripheral Nerves; Prealbumin; Preimplantation Diagnosis
PubMed: 28609277
DOI: 10.5935/1518-0557.20170025 -
General and Comparative Endocrinology May 2021In plasma, thyroid hormone (TH) is bound to several TH distributor proteins (THDPs), constituting a TH delivery/distribution network. Extensive studies of THDPs from... (Review)
Review
In plasma, thyroid hormone (TH) is bound to several TH distributor proteins (THDPs), constituting a TH delivery/distribution network. Extensive studies of THDPs from tetrapods has proposed an evolutionary scenario concerning structural and functional changes in THDPs, especially for transthyretin (TTR). When assessing, in an evolutionary context, the roles of THDPs as a component constituting part of the vertebrate thyroid system, the data from fish THDPs are critical. In this review the phylogenetic distributions, spatiotemporal expression patterns and binding properties of THDPs in fish are described, and the question of whether the evolutionary hypotheses proposed in tetrapod THDPs can be applied to fish THDPs is assessed. The phylogenetic distributions of THDPs are highly variable among fish groups. Analysis in this review reveals that the evolutionary hypotheses proposed in tetrapod THDPs cannot be applied to fish THDPs, and that the role of plasma lipoproteins as THDPs grows in importance in fish groups. In primitive fish, zinc is an import factor in TH binding to TTR, and high zinc content may facilitate the acquisition of high TH binding activity during the early evolution of TTR. Finally, the possible roles of THDPs in the vertebrate thyroid system are discussed.
Topics: Animals; Fishes; Phylogeny; Prealbumin; Thyroid Gland; Thyroid Hormones
PubMed: 33549607
DOI: 10.1016/j.ygcen.2021.113735 -
International Journal of Molecular... Jun 2019Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form... (Review)
Review
Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.
Topics: Amyloidogenic Proteins; Amyloidosis; Biomarkers; Diagnosis, Differential; Disease Management; Humans; Mutation; Prealbumin; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship; Workflow
PubMed: 31216785
DOI: 10.3390/ijms20122982 -
Current Problems in Cardiology Feb 2023Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin... (Review)
Review
Transthyretin cardiac amyloidosis is a restrictive cardiomyopathy caused by extracellular deposition in the heart of amyloid fibrils derived from plasma transthyretin (ATTR), either in its hereditary (ATTRh) or acquired (ATTRwt) forms. Cardiac amyloidosis has a very poor prognosis if therapy is not started promptly. Therefore, it is very important to recognize cardiac amyloidosis early in order to immediately start a treatment capable of modifying the prognosis. Treatment of cardiac amyloidosis is not easy, often requiring a multidisciplinary team. New RNA-interfering drugs (such as patisiran) have been devised and are effective in the treatment of ATTRh amyloidosis. Tafamidis (a stabilizer of the native tetramer structure of TTR) is recommended to treat patients with genetic testing-proven hereditary hTTR-cardiomyopathy or wild-type TTR cardiomyopathy and NYHA Class I or II to reduce symptoms, CV hospitalization and mortality (Class I, level of evidence B). Patisiran should be considered in ATTRh cardiomyopathy with polyneuropathy. Thus, this review is intended to be a simple practical guide for the treatment of ATTR cardiac amyloidosis.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Cardiomyopathies; Amyloid
PubMed: 36336119
DOI: 10.1016/j.cpcardiol.2022.101487 -
Cellular and Molecular Life Sciences :... Sep 2021Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol... (Review)
Review
Transthyretin (TTR) is an extracellular protein mainly produced in the liver and choroid plexus, with a well-stablished role in the transport of thyroxin and retinol throughout the body and brain. TTR is prone to aggregation, as both wild-type and mutated forms of the protein can lead to the accumulation of amyloid deposits, resulting in a disease called TTR amyloidosis. Recently, novel activities for TTR in cell biology have emerged, ranging from neuronal health preservation in both central and peripheral nervous systems, to cellular fate determination, regulation of proliferation and metabolism. Here, we review the novel literature regarding TTR new cellular effects. We pinpoint TTR as major player on brain health and nerve biology, activities that might impact on nervous systems pathologies, and assign a new link between TTR and angiogenesis and cancer. We also explore the molecular mechanisms underlying TTR activities at the cellular level, and suggest that these might go beyond its most acknowledged carrier functions and include interaction with receptors and activation of intracellular signaling pathways.
Topics: Amyloidosis; Central Nervous System; Humans; Neurons; Prealbumin; Protein Aggregates; Reactive Oxygen Species; Thyroxine; Vitamin A
PubMed: 34297165
DOI: 10.1007/s00018-021-03899-3 -
Journal of Integrative Neuroscience Nov 2023Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The... (Review)
Review
Transthyretin (TTR) is secreted by hepatocytes, retinal pigment epithelial cells, pancreatic α and β cells, choroid plexus epithelium, and neurons under stress. The choroid plexus product is the main transporter of the thyroid hormone thyroxine (T4) to the brain during early development. TTR is one of three relatively abundant cerebrospinal fluid (CSF) proteins (Apolipoprotein J [ApoJ] (also known as clusterin), Apolipoprotein E [ApoE], and TTR) that interact with Aβ peptides , in some instances inhibiting their aggregation and toxicity. It is now clear that clusterin functions as an extracellular, and perhaps intracellular, chaperone for many misfolded proteins and that variation in its gene () is associated with susceptibility to sporadic Alzheimer's disease (AD). The function of ApoE in AD is not yet completely understood, although the allele has the strongest genetic association with the development of sporadic late onset AD. Despite and evidence of the interaction between TTR and Aβ, genomewide association studies including large numbers of sporadic Alzheimer's disease patients have failed to show significant association between variation in the gene and disease prevalence. Early clinical studies suggested an inverse relationship between CSF TTR levels and AD and the possibility of using the reduced CSF TTR concentration as a biomarker. Later, more extensive analyses indicated that CSF TTR concentrations may be increased in some patients with AD. While the observed changes in TTR may be pathogenetically or biologically interesting because of the inconsistency and lack of specificity, they offered no benefit diagnostically or prognostically either independently or when added to currently employed CSF biomarkers, i.e., decreased Aβ1-42 and increased Tau and phospho-Tau. While some clinical data suggest that increases in CSF TTR may occur early in the disease with a significant decrease late in the course, without additional, more granular data, CSF TTR changes are neither consistent nor specific enough to warrant their use as a specific AD biomarker.
Topics: Humans; Alzheimer Disease; Clusterin; Prealbumin; Apolipoproteins E; Biomarkers; Amyloid beta-Peptides
PubMed: 38176942
DOI: 10.31083/j.jin2206158 -
European Heart Journal Jun 2023
Topics: Humans; Prealbumin; Amyloid Neuropathies, Familial; Cardiomyopathies; Radionuclide Imaging
PubMed: 37282599
DOI: 10.1093/eurheartj/ehad281 -
Computers in Biology and Medicine Mar 2023Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or...
Non-covalent intramolecular interactions play a key role in the protein folding process. Aminoacidic mutations or changes in physiological conditions such as pH and/or temperature variations can compromise intramolecular stability generating misfolding or unfolding proteins with consequent impairment of functionality and the triggering of pathological states. The intramolecular HINT scoring function recently implemented and validated, is proposed as a rapid and sensitive method for the evaluation of different conformational states characterizing destabilization processes. In this work, the stability of Transthyretin, whose denaturation is related to amyloid fibril formation, is evaluated by generating multiple structural mutated models under different pH conditions in comparison with experimental data. These results suggest that the HINT scoring function can be used for an accurate and rapid evaluation and computational prediction of the effects of structural changes on any protein system.
Topics: Prealbumin; Amyloid; Comprehension; Protein Denaturation; Protein Folding
PubMed: 36805224
DOI: 10.1016/j.compbiomed.2023.106667