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FEBS Letters Jun 2001Over 70 transthyretin (TTR) mutations have been associated with hereditary amyloidoses, which are all autosomal dominant disorders with adult age of onset. TTR is the... (Review)
Review
Over 70 transthyretin (TTR) mutations have been associated with hereditary amyloidoses, which are all autosomal dominant disorders with adult age of onset. TTR is the main constituent of amyloid that deposits preferentially in peripheral nerve giving rise to familial amyloid polyneuropathy (FAP), or in the heart leading to familial amyloid cardiomyopathy. Since the beginning of this decade the central question of these types of amyloidoses has been why TTR is an amyloidogenic protein with clinically heterogeneous pathogenic consequences. As a result of amino acid substitutions, conformational changes occur in the molecule, leading to weaker subunit interactions of the tetrameric structure as revealed by X-ray studies of some amyloidogenic mutants. Modified soluble tetramers exposing cryptic epitopes seem to circulate in FAP patients as evidenced by antibody probes recognizing specifically TTR amyloid fibrils, but what triggers dissociation into monomeric and oligomeric intermediates of amyloid fibrils is largely unknown. Avoiding tetramer dissociation and disrupting amyloid fibrils are possible avenues of therapeutic intervention based on current molecular knowledge of TTR amyloidogenesis and fibril structure.
Topics: Amyloidosis; Drug Design; Humans; Models, Molecular; Prealbumin; Protein Binding; Protein Conformation
PubMed: 11412857
DOI: 10.1016/s0014-5793(01)02480-2 -
Critical Reviews in Eukaryotic Gene... 2016Since transthyretin (TTR) was discovered, it has been regarded as a serum protein carrier of thyroid hormones and retinol. However, many other important functions of TTR... (Review)
Review
Since transthyretin (TTR) was discovered, it has been regarded as a serum protein carrier of thyroid hormones and retinol. However, many other important functions of TTR have been found recently, and current evidence suggests that it plays a role in human receptivity and normal pregnancy. TTR is abundant in the uterine cavity, uterine secretion, placenta, and serum of pregnant females in the peri-implantation uterus and the first trimester of pregnancy. It may be involved in the delivery of maternal thyroid hormones to the fetus. In addition, it appears to play a key role in the preeclampsia mechanism and may be involved in spiral artery remodeling. This review will summarize what is currently known about TTR and normal pregnancy; it will focus on our findings regarding the role of TTR in the spiral artery remodeling process and the additional research required in the future.
Topics: Carrier Proteins; Female; Humans; Placenta; Prealbumin; Pregnancy; Pregnancy Trimester, First; Thyroid Hormones; Trophoblasts
PubMed: 27650990
DOI: 10.1615/CritRevEukaryotGeneExpr.2016017323 -
The Journal of Clinical Investigation Jan 1988In the last several years, five human plasma prealbumin (transthyretin) variants have been discovered in association with hereditary amyloidosis, a late-onset fatal...
In the last several years, five human plasma prealbumin (transthyretin) variants have been discovered in association with hereditary amyloidosis, a late-onset fatal disorder. We recently studied a patient of German descent with peripheral neuropathy and bowel dysfunction. Biopsied rectal tissue contained amyloid that stained with anti-human prealbumin. Amino acid sequence analysis of the patient's plasma prealbumin revealed both normal and variant prealbumin molecules, with the variant containing a tyrosine at position 77 instead of serine. We predicted a single nucleotide change in codon 77 of the variant prealbumin gene, which we then detected in the patient's DNA using the restriction enzyme SspI and a specifically tailored genomic prealbumin probe. DNA tests of other family members identified several gene carriers. This is the sixth prealbumin variant implicated in amyloidosis, and adds to the accumulating evidence that the prealbumin amyloidoses are more varied and prevalent than previously thought.
Topics: Amyloidosis; DNA; Humans; Middle Aged; Pedigree; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prealbumin; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma
PubMed: 2891727
DOI: 10.1172/JCI113293 -
Biochemical and Biophysical Research... Jul 1983Amyloid fibrils from an individual with heredofamilial amyloidosis were found to be composed of plasma prealbumin. To study this protein a three step procedure to...
Amyloid fibrils from an individual with heredofamilial amyloidosis were found to be composed of plasma prealbumin. To study this protein a three step procedure to isolate prealbumin from plasma was developed. It entailed ion exchange chromatography on DEAE Sephadex, affinity chromatography on Affi-gel Blue and gel filtration on AcA-34. Trypsin Digests of prealbumin were separated by reverse phase HPLC and the pattern compared to that from the normal protein. Only one unexpected peptide was found and it represented the substitution of a methionine for a valine at position 30 in the molecule. This substitution accounts for about 1/3 of the isolated molecules and it represents the first point mutation identified in human plasma prealbumin.
Topics: Amino Acid Sequence; Amyloidosis; Humans; Peptide Fragments; Polymorphism, Genetic; Prealbumin
PubMed: 6882448
DOI: 10.1016/0006-291x(83)90831-8 -
General and Comparative Endocrinology Sep 2000Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR... (Review)
Review
Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-l-thyronine.
Topics: Amino Acid Sequence; Animals; DNA, Complementary; Evolution, Molecular; Humans; Models, Molecular; Molecular Sequence Data; Molecular Structure; Phylogeny; Prealbumin; Sequence Homology
PubMed: 11017772
DOI: 10.1006/gcen.2000.7520 -
Clinical Chemistry and Laboratory... Dec 2002Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles,... (Review)
Review
Thyroid hormones are essential for normal mammalian development and for normal metabolism. Thyroxine (T4) is the principal product synthesized by the thyroid follicles, and triiodothyronine (T3), the biologically active hormone, derives mainly from tissue T4 deiodination. More than 99% of the circulating hormone is bound to plasma proteins, mainly to thyroxine-binding globulin, transthyretin and albumin in man, and to transthyretin and albumin in rodents. The role of plasma proteins in the transport of hormones to target tissues has, for a long time, been controversial. The liver and the choroid plexus are the major sites of transthyretin synthesis, tissues from which transthyretin is secreted into the blood and the cerebrospinal fluid, respectively. Transthyretin has been proposed to mediate thyroid hormone transfer into the tissues, particularly into the brain across the choroid-plexus-cerebrospinal fluid barrier. Studies in a transthyretin-null mice strain have shown conclusively that transthyretin is not indespensable for thyroid hormones' entry into the brain and other tissues, nor for the maintenance of an euthyroid status. An euthyroid status is also observed in man totally deprived of thyroxine-binding globulin and in rats without albumin. Taken together, these results exclude dependence of thyroid hormone homeostasis on any major plasma carrier per se. This evidence agrees with the free hormone hypothesis which states that the biologically significant fraction, that is taken up by the tissues, is the free circulating hormone.
Topics: Animals; Brain; Carrier Proteins; Humans; Prealbumin; Thyroid Hormones
PubMed: 12553433
DOI: 10.1515/CCLM.2002.223 -
Aging Cell Dec 2017Deposition of amyloid is a common aging-associated phenomenon in several aging-related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is...
Deposition of amyloid is a common aging-associated phenomenon in several aging-related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA-affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild-type human TTR (hTTR-TG). Although TTR protein was detected in cartilage in hTTR-TG mice, the TTR transgene was highly overexpressed in liver, but not in chondrocytes. OA was surgically induced by destabilizing the medial meniscus (DMM) in hTTR-TG mice, wild-type mice of the same strain (WT), and mice lacking endogenous Ttr genes. In the DMM model, both cartilage and synovitis histological scores were significantly increased in hTTR-TG mice. Further, spontaneous degradation and OA-like changes in cartilage and synovium developed in 18-month-old hTTR mice. Expression of cartilage catabolic (Adamts4, Mmp13) and inflammatory genes (Nos2, Il6) was significantly elevated in cartilage from 6-month-old hTTR-TG mice compared with WT mice as was the level of phospho-NF-κB p65. Intra-articular injection of aggregated TTR in WT mice increased synovitis and significantly increased expression of inflammatory genes in synovium. These findings are the first to show that TTR deposition increases disease severity in the murine DMM and aging model of OA.
Topics: Age Factors; Animals; Disease Models, Animal; Disease Progression; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Osteoarthritis; Prealbumin
PubMed: 28941045
DOI: 10.1111/acel.12665 -
Current Medicinal Chemistry 2012Among the 23 different fibril proteins described in human amyloidosis, transthyretin is associated with the most common hereditary form of the disease and its knowledge... (Review)
Review
Among the 23 different fibril proteins described in human amyloidosis, transthyretin is associated with the most common hereditary form of the disease and its knowledge is corroborated through about 150 crystal structures in addition to thousands of small ligands tested as fibril formation inhibitors. In spite of the large amount of available data, the mechanism of transthyretin aggregation and its inhibition through binding with small ligands is not clear. In the last decade, many groups of researchers have attempted to apply computational procedures to simulate these phenomena, with the aim of understanding them in depth and in order to rationalize the design of new promising inhibitors. A summary of the main molecular dynamics, docking, and structure-activity relationship studies carried out on transthyretin are reviewed here, and the most successful results and new trends are described in detail.
Topics: Amyloid; Amyloidosis; Computer Simulation; Humans; Models, Molecular; Prealbumin; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 22471985
DOI: 10.2174/092986712800269344 -
Clinical Chemistry and Laboratory... Dec 2002The history of prealbumin dates back to the early forties and may be divided into three parts, based on a chronological and functional approach. The first part--the... (Review)
Review
The history of prealbumin dates back to the early forties and may be divided into three parts, based on a chronological and functional approach. The first part--the discovery and the identification of prealbumin--was essentially based on classical protein chemistry methods. The second--the demonstration of prealbumin as a thyroid hormone-binding protein (thyroxine-binding prealbumin)--has greatly benefited from isotopic techniques. The third one--establishing prealbumin as a nutritional marker--was a result of field studies on nutrition. The discovery of the role of prealbumin in retinol binding led to a change in its name, prealbumin becoming transthyretin. Finally, structural studies and mutation analysis of transthyretin in patients with amyloid neuropathy have opened a new area of research.
Topics: Amyloid Neuropathies; Animals; Humans; Mutation; Prealbumin; Protein Binding; Thyroxine-Binding Proteins
PubMed: 12553430
DOI: 10.1515/CCLM.2002.220 -
Mini Reviews in Medicinal Chemistry 2024Transthyretin amyloid cardiomyopathy and Transthyretin amyloid peripheral neuropathy are progressive disease conditions caused by Transthyretin amyloidosis (ATTR) fibril... (Review)
Review
Transthyretin amyloid cardiomyopathy and Transthyretin amyloid peripheral neuropathy are progressive disease conditions caused by Transthyretin amyloidosis (ATTR) fibril infiltration in the tissue. Transthyretin (TTR) protein misfolding and amyloid fibril deposits are pathological biomarkers of ATTR-related disorders. There are various treatment strategies targeting different stages in pathophysiology. One such strategy is TTR tetramer stabilization. Recently, a new TTR tetramer stabilizer, tafamidis, has been introduced that reduces the protein misfolding and amyloidosis and, consequently, disease progression in ATTR cardiomyopathy and peripheral neuropathy. This review will provide a comprehensive overview of the literature on tafamidis discovery, development, synthetic methods, pharmacokinetics, analytical methods and clinical trials. Overall, 7 synthetic methods, 5 analytical methods and 23 clinical trials have been summarized from the literature.
Topics: Humans; Benzoxazoles; Amyloid Neuropathies, Familial; Prealbumin; Animals
PubMed: 37828667
DOI: 10.2174/0113895575241556231003055323