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JPEN. Journal of Parenteral and Enteral... 1986
Topics: Humans; Nutritional Physiological Phenomena; Prealbumin
PubMed: 3747097
DOI: 10.1177/0148607186010004435 -
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 -
Cellular and Molecular Life Sciences :... Sep 2001Transthyretin (formerly called prealbumin) plays important physiological roles as a transporter of thyroxine and retinol-binding protein. X-ray structural studies have... (Review)
Review
Transthyretin (formerly called prealbumin) plays important physiological roles as a transporter of thyroxine and retinol-binding protein. X-ray structural studies have provided information on the active conformation of the protein and the site of binding of both ligands. Transthyretin is also one of the precursor proteins commonly found in amyloid deposits. Both wild-type and single-amino-acid-substituted variants have been identified in amyloid deposits, the variants being more amyloidogenic. Sequencing of the gene and the resulting production of a transgenic mouse model have resulted in progress toward solving the mechanism of amyloid formation and detecting the variant gene in individuals at risk.
Topics: Animals; Biological Transport; Crystallography, X-Ray; Genetic Variation; Humans; Ligands; Mice; Mice, Transgenic; Models, Molecular; Prealbumin; Protein Binding; Protein Conformation; Recombinant Proteins; Thyroxine
PubMed: 11693529
DOI: 10.1007/PL00000791 -
International Review of Neurobiology 2009Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid plexus, is mainly known as the physiological carrier of thyroxine (T(4))... (Review)
Review
Transthyretin (TTR), a plasma and cerebrospinal fluid protein secreted by the liver and choroid plexus, is mainly known as the physiological carrier of thyroxine (T(4)) and retinol. Under pathological conditions, various TTR mutations are related to familial amyloid polyneuropathy (FAP), a neurodegenerative disorder characterized by deposition of TTR amyloid fibrils, particularly in the peripheral nervous system (PNS), leading to axonal loss and neuronal death. Recently, a number of TTR functions in neurobiology have been described; these may explain the preferential TTR deposition, when mutated, in the PNS of FAP patients. In this respect, and with a particular relevance in the PNS, TTR has been shown to have the ability to enhance neurite outgrowth in vitro and nerve regeneration following injury, in vivo. In the following pages, this novel TTR function, as well as its importance in nerve biology and repair will be discussed.
Topics: Amyloid Neuropathies, Familial; Animals; Humans; Mice; Mice, Knockout; Mutation; Nerve Regeneration; Neurites; Peripheral Nerve Injuries; Peripheral Nerves; Prealbumin; Time Factors
PubMed: 19682646
DOI: 10.1016/S0074-7742(09)87017-7 -
The FEBS Journal Oct 2009
Topics: Animals; Evolution, Molecular; Humans; Prealbumin
PubMed: 19725884
DOI: 10.1111/j.1742-4658.2009.07242.x -
Expert Reviews in Molecular Medicine May 2002Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a... (Review)
Review
Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a conformational change and form amyloid fibrils, in both acquired and hereditary forms of systemic amyloidosis. More than 80 TTR mutations have been associated with autosomal dominant amyloidosis, usually presenting with peripheral and autonomic neuropathy and/or cardiomyopathy. Major areas of research in TTR amyloidosis include: molecular mechanisms leading to fibril formation; mechanisms of fibril-induced cell death; modulators of phenotypic expression of the disease; and therapeutic strategies.
Topics: Amyloid; Amyloidosis, Familial; Cell Death; Dimerization; Drug Therapy; Genetic Predisposition to Disease; Genetic Therapy; Humans; Liver Transplantation; Models, Molecular; Mutation; Phenotype; Prealbumin; Protein Conformation
PubMed: 14987380
DOI: 10.1017/S1462399402004647 -
Neuroscience Letters May 1986We have investigated the expression of the gene for transthyretin (prealbumin) in the human choroid plexus. RNA was isolated from the human choroid plexus, fractionated... (Comparative Study)
Comparative Study
We have investigated the expression of the gene for transthyretin (prealbumin) in the human choroid plexus. RNA was isolated from the human choroid plexus, fractionated by electrophoresis in agarose gel and transferred onto a nitrocellulose filter membrane. Transthyretin messenger RNA (mRNA) was identified by hybridization to radioactive complementary DNA for rat transthyretin. The level of transthyretin mRNA in the human choroid plexus was found to be at least 40 times higher than in human liver, suggesting very active synthesis of transthyretin in the choroid plexus.
Topics: Animals; Choroid Plexus; DNA; Electrophoresis, Agar Gel; Gene Expression Regulation; Humans; Liver; Nucleic Acid Hybridization; Prealbumin; RNA, Messenger; Rats
PubMed: 3755228
DOI: 10.1016/0304-3940(86)90037-6 -
Current Opinion in Structural Biology Feb 2010Small molecules that bind to normally unoccupied thyroxine (T(4)) binding sites within transthyretin (TTR) in the blood stabilize the tetrameric ground state of TTR... (Review)
Review
Small molecules that bind to normally unoccupied thyroxine (T(4)) binding sites within transthyretin (TTR) in the blood stabilize the tetrameric ground state of TTR relative to the dissociative transition state and dramatically slow tetramer dissociation, the rate-limiting step for the process of amyloid fibril formation linked to neurodegeneration and cell death. These so-called TTR kinetic stabilizers have been designed using structure-based principles and one of these has recently been shown to halt the progression of a human TTR amyloid disease in a clinical trial, providing the first pharmacologic evidence that the process of amyloid fibril formation is causative. Structure-based design has now progressed to the point where highly selective, high affinity TTR kinetic stabilizers that lack undesirable off-target activities can be produced with high frequency.
Topics: Amyloidosis; Animals; Drug Design; Humans; Kinetics; Prealbumin; Protein Stability; Thyroxine
PubMed: 20133122
DOI: 10.1016/j.sbi.2009.12.009 -
Biological & Pharmaceutical Bulletin 2018Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR...
Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR tetramer protein to dissociate to monomer, which is the rate-limiting step in familial amyloid polyneuropathy. Amyloidogenicity of individual TTR variants depends on the types of mutation that induce significant changes in biophysical, biochemical and/or biological properties. G101S TTR variant was previously identified in a Japanese male without amyloidotic symptom, and was considered as a non-amyloidogenic TTR variant. However, little is known about G101S TTR. Here, we found slight but possibly important biophysical differences between wild-type (WT) and G101S TTR. G101S TTR had slower rate of tetramer dissociation and lower propensity for amyloid fibril formation, especially at mild low pH (4.2 and 4.5), and was likely to have strong hydrophobic interaction among TTR monomers, suggesting relatively higher stability of G101S TTR compared with WT TTR. Cycloheximide (CHX)-based assay in HEK293 cells revealed that intracellular G101S TTR expression level was lower, but extracellular expression was higher than WT TTR, implying enhanced secretion efficiency of G101S TTR protein compared with WT TTR. Moreover, we found that STT3B-dependent posttranslational N-glycosylation at N98 residue occurred in G101S TTR but not in other TTR variants, possibly due to amino acid alterations that increase N-glycosylation preference or accelerate rigid structure formation susceptible to N-glycosylation. Taken together, our study characterizes G101S TTR as a stable and N-glycosylable TTR, which may be linked to its non-amyloidogenic characteristic.
Topics: Amyloid; Amyloid Neuropathies, Familial; Glycosylation; HEK293 Cells; HeLa Cells; Hexosyltransferases; Humans; Membrane Proteins; Prealbumin
PubMed: 29607936
DOI: 10.1248/bpb.b17-01021 -
Neurotherapeutics : the Journal of the... Oct 2021The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis.... (Review)
Review
The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis. Recently approved agents and drugs currently under investigation not only represent a major breakthrough in this field but also provide validation of the therapeutic potential of innovative approaches, like RNA interference and CRISPR-Cas9-mediated gene editing, in rare inherited disorders. In this review, we describe the evolving therapeutic landscape for hereditary transthyretin amyloidosis and discuss how this highly disabling and fatal condition is turning into a treatable disease. We also provide an overview of the molecular mechanisms involved in transthyretin (TTR) amyloid formation and regression, to highlight how a deeper understanding of these processes has contributed to the identification of novel treatment targets. Finally, we focus on major areas of uncertainty and unmet needs that deserve further efforts to improve long-term patients' outcomes and allow for a brighter future.
Topics: Amyloid Neuropathies, Familial; Gene Editing; Humans; Prealbumin; RNA Interference
PubMed: 34850359
DOI: 10.1007/s13311-021-01154-y