TTR
Transthyretin precursor (ATTR) (Prealbumin) (TBPA) [PALB]
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Transthyretin amyloidosis (ATTR) is a progressive life-threatening disease characterized by the deposition of transthyretin (TTR) amyloid fibrils. Several pathogenic variants have been shown to destabilize TTR tetramers, leading to aggregation of misfolded TTR fibrils. However, factors that underlie the differential age of disease onset amongst amyloidogenic TTR variants remain elusive. Here, we examined the biological properties of various TTR mutations and found that the cellular secretory pattern of the wild-type (WT) TTR was similar to those of the late-onset mutant (Ala97Ser, p. Ala117Ser), stable mutant (Thr119Met, p. Thr139Met), early-onset mutant (Val30Met, p. Val50Met), but not in the unstable mutant (Asp18Gly, p. Asp38Gly). Cytotoxicity assays revealed their toxicities in the order of Val30Met > Ala97Ser > WT > Thr119Met in neuroblastoma cells. Surprisingly, while early-onset amyloidogenic TTR monomers (M-TTRs) are retained by the endoplasmic reticulum quality control (ERQC), late-onset amyloidogenic M-TTRs can be secreted extracellularly. Treatment of thapsigargin (Tg) to activate the unfolded protein response (UPR) alleviates Ala97Ser M-TTR secretion. Interestingly, Ala97Ser TTR overexpression in Drosophila causes late-onset fast neurodegeneration and a relatively short lifespan, recapitulating human disease progression. Our study demonstrates that the escape of TTR monomers from the ERQC may underlie late-onset amyloidogenesis in patients and suggests that targeting ERQC could mitigate late-onset ATTR.
MeSH Terms
- Amyloid Neuropathies, Familial
- Animals
- Cell Death
- Cell Line, Tumor
- Disease Models, Animal
- Drosophila
- HEK293 Cells
- Humans
- Locomotion
- Longevity
- Mutant Proteins
- Mutation
- Nerve Degeneration
- Prealbumin
Keywords
- Amyloidosis
- Drosophila melanogaster
- ERQC
- Endoplasmic reticulum quality control
- Proteostasis
- TTR
- Transthyretin
Familial amyloid polyneuropathy is a hereditary systemic amyloidosis caused by a mutation in the transthyretin (TTR) gene. Amyloid deposits in tissues of patients contain not only full-length TTR but also C-terminal TTR fragments. However, in vivo models to evaluate the pathogenicity of TTR fragments have not yet been developed. Here, we generated transgenic Caenorhabditis elegans strains expressing several types of TTR fragments or full-length TTR fused to enhanced green fluorescent protein in the body wall muscle cells and analyzed the phenotypes of the worms. The transgenic strain expressing residues 81-127 of TTR, which included the β-strands F and H, formed aggregates and caused defective worm motility and a significantly shortened lifespan compared with other strains. These findings suggest that the C-terminal fragments of TTR may contribute to cytotoxicity of TTR amyloidosis in vivo. By using this C. elegans model system, we found that (-)-epigallocatechin-3-gallate, a major polyphenol in green tea, significantly inhibited the formation of aggregates, the defective motility, and the shortened lifespan caused by residues 81-127 of TTR. These results suggest that our newly developed C. elegans model system will be useful for in vivo pathological analyses of TTR amyloidosis as well as drug screening.
MeSH Terms
- Amyloid Neuropathies, Familial
- Animals
- Animals, Genetically Modified
- Caenorhabditis elegans
- Catechin
- Disease Models, Animal
- Drug Evaluation, Preclinical
- Green Fluorescent Proteins
- Humans
- Locomotion
- Longevity
- Neuroprotective Agents
- Prealbumin
- Recombinant Fusion Proteins
- Staining and Labeling
Central nervous system (CNS) involvement in hereditary transthyretin (TTR) amyloidosis has been described in patients whose disease course was modified by liver transplant. However, cognitive dysfunction has yet to be investigated in those patients. Moreover, CNS involvement in untreated patients or asymptomatic mutation carriers remains to be studied. A series of 340 carriers of the TTRVal30Met mutation (180 symptomatic and 160 asymptomatic) underwent a neuropsychological assessment, which included the Dementia Rating Scale-2 (DRS-2), auditory verbal learning test, semantic fluency, phonemic fluency, and trail making test. Cognitive deficits were identified at the individual level, after adjusting the neuropsychological test scores for demographic characteristics (sex, age, and education), based on large national normative data. The presence of cognitive dysfunction was determined by deficit in DRS-2 and/or multiple cognitive domains. Participants were also screened for depression based on a self-report questionnaire. The frequency of cognitive dysfunction was higher (p = 0.003) in symptomatic (9%) than in asymptomatic (2%) carriers. Among older carriers (≥ 50 years), the frequency of cognitive dysfunction was higher (p < 0.001) in symptomatic (36%) than asymptomatic (4%) individuals. Among younger participants (< 50 years), the frequency of cognitive dysfunction was not different (p = 0.631) between symptomatic patients (2%) and asymptomatic (1%) carriers. This cross-sectional study shows that cognitive dysfunction is part of the broad spectrum of clinical manifestations in older hereditary TTR amyloidosis patients with peripheral polyneuropathy, even in the early stages of the disease.
MeSH Terms
- Adult
- Age of Onset
- Aging
- Amyloid Neuropathies, Familial
- Anxiety
- Chi-Square Distribution
- Cognition Disorders
- Depression
- Female
- Humans
- Male
- Methionine
- Middle Aged
- Mutation
- Neurologic Examination
- Neuropsychological Tests
- Prealbumin
- Statistics, Nonparametric
- Valine
Keywords
- Aging
- Amyloidosis
- Cognition
- Dementia
- Familial amyloidotic polyneuropathy
- Transthyretin
Administration of alpha-glycerophosphocholine (GPC), a choline compound in food, is expected to contribute to human health. In this study, we evaluated its effect on aging in senescence-accelerated mouse prone 8 (SAMP8) mice. Male SAMP8 mice had free access to a commercial stock diet and drinking water with or without GPC (0.07 mg/ml). Mice in the GPC group had significantly lower total senescence grading score than that of the control group at 36 weeks of age. Administration of GPC decreased the deposition of transthyretin (TTR), an amyloidogenic protein, in the brain. Aggregated TTR activated microglia and led to neuroinflammation. Thus, GPC would protect the brain by reducing TTR deposition and preventing neuroinflammation. In a histological study of knee joints, it was found that SAMP8 mice administered GPC showed decreased joint degeneration. These results suggest that GPC delays the aging process and may be a useful compound in anti-aging functional food development.
MeSH Terms
- Aging
- Amyloid beta-Peptides
- Animals
- Brain
- Dietary Supplements
- Disease Models, Animal
- Disease Progression
- Functional Food
- Glycerylphosphorylcholine
- Male
- Maze Learning
- Mice, Mutant Strains
- Osteoarthritis, Knee
- Prealbumin
Keywords
- Aging
- alpha-glycerophosphocholine
- amyloid beta
- osteoarthritis
- transthyretin
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.
MeSH Terms
- Age Factors
- Animals
- Disease Models, Animal
- Disease Progression
- Humans
- Immunohistochemistry
- Male
- Mice
- Mice, Transgenic
- Osteoarthritis
- Prealbumin
Keywords
- aging
- amyloid
- cartilage
- osteoarthritis
- transthyretin
To describe the quality of warfarin use in residents of long-term care facilities and investigate potential predictors oral anticoagulant use. Retrospective chart review (August 2013 to September 2014). Thirteen long-term care (LTC) and assisted living facilities (ALF). Residents from LTC or ALF settings who ( a) received warfarin or direct-acting oral anticoagulants (DOACs) and ( b) residents with a valid indication for oral anticoagulants such as atrial fibrillation, venous thromboembolism, but were not receiving these drugs. Time in therapeutic international normalized ratio (INR) range (TTR). A total of 563 residents (70% female) with an average age of 85 years were identified. Participants had an average of 7.5 comorbidities and 9 medications. A total of 391 (69%) residents with indications for OACs were receiving such medications. Indications were atrial fibrillation (63%), venous or pulmonary embolism (16%), cardiac valves (0.4%); 26% did not have documented indications. Warfarin and DOACs were prescribed for 213 (38%) and 178 (32%) respectively, and 172 (31%) received no OACs The TTR ranged from 56%-75% (mean 63%). The frequency of INR determinations ranged from every 7 to 20 days, (mean 13 days) with no apparent relationship between frequency of testing and TTR. The TTR was higher (63.8%) than literature average (50%), but remains suboptimal given expected benefits of TTRs >75% versus TTRs circa 60%. Documentation of indications for OACs needs improvement, and it is possible that OACs are underused. Further work is necessary to understand how OAC use may be optimized in these facilities.
MeSH Terms
- Administration, Oral
- Aged
- Aged, 80 and over
- Anticoagulants
- Assisted Living Facilities
- Atrial Fibrillation
- Drug Utilization
- Female
- Humans
- International Normalized Ratio
- Long-Term Care
- Male
- Retrospective Studies
- Venous Thromboembolism
- Warfarin
Keywords
- assisted living
- atrial fibrillation
- drug utilization
- geriatrics
- long-term care
- oral anticoagulants
- quality
- stroke
Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits. We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that ∼16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amyloid
- Amyloidosis
- Apolipoprotein A-I
- Cartilage, Articular
- Female
- Humans
- Knee Joint
- Male
- Osteoarthritis, Knee
- Prealbumin
- Synovial Fluid
Keywords
- Apolipoprotein A-I
- articular cartilage
- knee joint
- knee osteoarthritis
- meniscus
- synovial membrane
- transthyretin
Domino liver transplantation (DLT) with liver grafts from patients with hereditary transthyretin (TTR) amyloidosis has been performed throughout the world because of a severe liver graft shortage. Reports of acquired systemic TTR amyloidosis in domino liver recipients have been increasing; however, the precise pathogenesis and clinical course of acquired TTR amyloidosis remains unclear. We analyzed the relationship between the occurrence of acquired amyloidosis and clinical features in 22 consecutive domino liver donors with hereditary TTR amyloidosis (10 males and 12 females; mean age at DLT: 37.2 years; TTR mutations: V30M [n = 19], Y114C [n = 1], L55P [n = 1], and S50I [n = 1]) and 22 liver recipients (16 males and 6 females; mean age at DLT, 46.2 years). The mean times from DLT to amyloid first appearance and transplant recipient symptom onset were 8.2 years and 9.9 years, respectively. Kaplan-Meier analysis and quantification of the amyloid deposition revealed aging of recipients correlated with early de novo amyloid deposition. The sex of donors and recipients and the age, disease duration, and disease severity of donors had no significant effect on the latency of de novo amyloid deposition. In conclusion, our results demonstrate that recipient aging is associated with the early onset de novo amyloidosis. Because acquired amyloidosis will likely increase, careful follow-up for early amyloidosis detection and new treatments, including TTR stabilizers and gene-silencing therapies, are required. Liver Transplantation 22 656-664 2016 AASLD.
MeSH Terms
- Adult
- Aging
- Amyloid Neuropathies, Familial
- Amyloidosis
- Female
- Humans
- Kaplan-Meier Estimate
- Liver Transplantation
- Male
- Middle Aged
- Mutation
- Prealbumin
- Time Factors
- Tissue Donors
- Transplant Recipients
Plasma concentrations of transthyretin (TTR), a negative acute-phase protein, can be influenced by many factors including aging. Under physiological circumstances, TTR concentrations are very low in the fetus, increase slowly after birth up to the fifth decade and, then, decrease slowly. Some studies have shown sex-related differences up to about 70 years, when the differences disappear. The aim of this study was to evaluate the change in TTR concentrations in healthy males and females aged more than sixty, including numerous centenarians living in Sardinia, a large Italian island located in the Mediterranean Sea. The study sample consisted of 211 healthy subjects grouped by age and sex (male/female ratio: 1:1). Plasma TTR was assessed using a non-competitive enzyme immunoassay (ELISA Assaypro LLC, prealbumin AssayMAX Human ELISA Kit). In subjects aged between 60 and 99 years, plasma TTR concentrations were higher compared to the reference ranges reported by CRM 470. Moreover, unlike other studies, sex-related differences in TTR concentrations were only observed in nonagenarians and centenarians. We hypothesize that there are TTR-related genetic differences between the Sardinian population and other Caucasian ethnic groups. Further studies and a larger sample are needed to confirm our hypothesis.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Female
- Humans
- Italy
- Male
- Middle Aged
- Prealbumin
- Sex Factors
Keywords
- Aging
- Centenarians
- Sardinia
- Transthyretin
Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR amyloidosis is liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers, diflunisal and tafamidis, were demonstrated in randomised clinical trials, and tafamidis has been approved for treatment of hereditary ATTR amyloidosis in European countries and in Japan. Moreover, antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR amyloidosis and are currently in phase III clinical trials. These newly developed therapies are expected to be effective for not only hereditary ATTR amyloidosis but also wild-type ATTR amyloidosis.
MeSH Terms
- Amyloid Neuropathies, Familial
- Benzoxazoles
- Diflunisal
- Humans
- Mutation
- Prealbumin
Keywords
- AMYLOID
- GENETICS
- GERIATRICS
- NEUROGENETICS
- NEUROPATHY
Warfarin-treated patients with poor international normalized ratio (INR) control, measured with time in therapeutic range (TTR) or the standard deviation of transformed INR (SDTINR), have an increased risk for clinical events. To what extent only a short period with an altered INR control may influence outcomes remains unknown. This study assessed the impact of transient periods of worsened or improved INR control on life expectancy and quality-adjusted life years (QALYs) among warfarin-treated patients with atrial fibrillation (AF) using both metrics. Warfarin-treated patients with AF, registered in the patient record system Journalia during years 1985-2000, were included. Information on all-cause mortality was collected from the Cause of Death Register. Hypothetical scenarios where patients were assumed to have a transiently altered INR control during 30days were modeled statistically using hazard functions, and the impact on remaining life expectancy and QALYs was assessed. When using SDTINR, a 70-year old man within the 20th best INR control percentile was estimated to lose 7.4days of life or 0.0100 QALYs from a 30-day long worsened INR control to that of an average 70-year old male patient. Correspondingly, 4.0days of life or 0.0059 QALYs would be gained if a 70-year old man within the 20th worst INR control percentile would have an average INR control during 30days. The magnitudes were smaller when TTR was used to determine INR control. Even short periods of an altered INR control is expected to have impact on life expectancy and QALYs among patients with AF.
MeSH Terms
- Aged
- Atrial Fibrillation
- Female
- Humans
- International Normalized Ratio
- Life Expectancy
- Male
- Quality-Adjusted Life Years
- Warfarin
Keywords
- Atrial fibrillation
- International normalized ratio
- Quality-adjusted life years
- Warfarin
Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.
MeSH Terms
- Adult
- Amyloid
- Antibodies, Catalytic
- Antibody Specificity
- Female
- Humans
- Immunoglobulin M
- Male
- Prealbumin
- Proteolysis
Keywords
- Aging
- Amyloid
- Amyloidosis
- Antibodies
- Catalytic Antibody
- Innate Immunity
- Protein Evolution
- Superantigen
- Transthyretin
The posttranscriptional regulation of gene expression occurs through cis RNA regulatory elements by the action of trans factors, which are represented by noncoding RNAs (especially microRNAs) and turnover- and translation-regulatory (TTR) RNA-binding proteins (RBPs). These multifactorial proteins are a group of heterogeneous RBPs primarily implicated in controlling the decay and translation rates of target mRNAs. TTR-RBPs usually shuttle between cellular compartments (the nucleus and cytoplasm) in response to various stimuli and undergo posttranslational modifications such as phosphorylation or methylation to ensure their proper subcellular localization and function. TTR-RBPs are emerging as key regulators of a wide variety of genes influencing kidney physiology and pathology. This review summarizes the current knowledge of TTR-RBPs that influence renal metabolism. We will discuss the role of TTR-RBPs as regulators of kidney ischemia, fibrosis and matrix remodeling, angiogenesis, membrane transport, immunity, vascular tone, hypertension, and acid-base balance as well as anemia, bone mineral disease, and vascular calcification.
MeSH Terms
- Acid-Base Equilibrium
- Aging
- Animals
- ELAV Proteins
- Heterogeneous Nuclear Ribonucleoprotein D0
- Heterogeneous-Nuclear Ribonucleoprotein D
- Humans
- Kidney
- MicroRNAs
- Neovascularization, Physiologic
- Poly(A)-Binding Proteins
- Protein Processing, Post-Translational
- RNA, Messenger
- RNA-Binding Proteins
- T-Cell Intracellular Antigen-1
- Tristetraprolin
- Vascular Calcification
- Y-Box-Binding Protein 1
Keywords
- RNA turnover
- RNA-binding protein
- nephrology
- renal
Age and sex differences are closely related to the onset of senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR). However, the effects of these differences on the amyloid formation mechanism in familial amyloid polyneuropathy (FAP) caused by variant TTR, have remained unclear. To elucidate age and sex differences in FAP, we investigated biochemical characteristics of amyloid deposits in different tissue sites of FAP by proteomic analysis. We used shotgun liquid chromatography/tandem mass spectrometry to analyze the proportions of variant and WT TTR in amyloid deposits in different tissues, such as cardiac, kidney, peripheral nerves, and gastrointestinal tissues, from 23 autopsied FAP cases. The analysis revealed a highly significant correlation between the proportion of WT TTR and age at autopsy in cardiac tissues, whereas the analysis indicated no correlation in kidney, peripheral nerves, and gastrointestinal tissues. In addition, we demonstrated age-related significantly increased WT TTR deposits, but not variant TTR deposits, in cardiac tissues of male patients. Taken together, these data suggest that both age and sex differences affect cardiac amyloid formation, mainly derived from WT TTR, in FAP.
MeSH Terms
- Adult
- Age Factors
- Amyloid Neuropathies, Familial
- Female
- Humans
- Male
- Middle Aged
- Myocardium
- Prealbumin
- Proteomics
- Sex Characteristics
- Young Adult
Keywords
- Aging
- Amyloidosis
- Familial amyloidotic polyneuropathy
- Proteome
- Sex differences
- Transthyretin
We aimed to evaluate the quality and determinants of vitamin K antagonists (VKA) control among very elderly patients in geriatric settings. A national cross-sectional survey was conducted among patients aged ≥80 years who were hospitalized in rehabilitation care or institutionalized in a nursing home and who were treated by VKA. Time in therapeutic range (TTR) was computed according to Rosendaal's method. A total of 2,633 patients were included. Mean [± standard deviation (SD)] age was 87.2 ± 4.4 years and 72.9 % were women. The main indication for VKA therapy was atrial fibrillation (AF; 71.4 %). Mean (±SD) TTR was 57.9 ± 40.4 %. After backward logistic regression, poorer VKA control (TTR <50 vs. ≥50 %) was associated with being hospitalized in rehabilitation care [odds ratio (OR)(rehab. vs. nursing home) = 1.41; 95 % CI 1.11-1.80], the indication for VKA treatment (OR(prosthetic heart valve vs. AF) = 4.76; 95 % CI 2.83-8.02), a recent VKA prescription (OR(<1 vs. >12 months) = 1.70; 95 % CI 1.08-2.67), the type of VKA (OR(fluindione vs. warfarin) = 1.22; 95 % CI 1.00-1.49), a history of international normalized ratio >4.5 (OR = 1.50; 95 % CI 1.21-1.84), a history of major bleeding (OR = 1.88; 95 % CI 1.00-3.53), antibiotic use (OR = 1.83; 95 % CI 1.24-2.70), and falls (OR(≥2 falls during the past year vs. <2) = 1.26; 95 % CI 1.01-1.56). Overall, VKA control remains insufficient in very old patients. Poorer VKA control was associated with taking VKA for a prosthetic heart valve, a recent VKA prescription, the use of other VKAs than warfarin, a history of overcoagulation and major bleeding, antibiotic use, and falls.
MeSH Terms
- Aged, 80 and over
- Anticoagulants
- Atrial Fibrillation
- Cross-Sectional Studies
- Drug Utilization Review
- Female
- France
- Geriatrics
- Humans
- Logistic Models
- Male
- Societies, Medical
- Surveys and Questionnaires
- Vitamin K
The transthyretin amyloidoses are diseases of protein misfolding characterized by the extracellular deposition of fibrils and other aggregates of the homotetrameric protein transthyretin (TTR) in peripheral nerves, heart, and other tissues. Age is the major risk factor for the development of these diseases. We hypothesized that an age-associated increase in the level of protein oxidation could be involved in the onset of the senile forms of the TTR amyloidoses. To test this hypothesis, we have produced and characterized relevant age-related oxidative modifications of the wild type (WT) and the Val122Ile (V122I) TTR variant, both involved in cardiac TTR deposition in the elderly. Our studies show that methionine/cysteine-oxidized TTR and carbonylated TTR from either the WT or the V122I variant are thermodynamically less stable than their nonoxidized counterparts. Moreover, carbonylated WT and carbonylated V122I TTR have a stronger propensity to form aggregates and fibrils than WT and V122I TTR, respectively, at physiologically attainable pH values. It is well-known that TTR tetramer dissociation, the limiting step for aggregation and amyloid fibril formation, can be prevented by small molecules that bind the TTR tetramer interface. Here, we report that carbonylated WT TTR is less amenable to resveratrol-mediated tetramer stabilization than WT TTR. All the oxidized forms of TTR tested are cytotoxic to a human cardiomyocyte cell line known to be a target for cardiac-specific TTR variants. Overall, these studies demonstrate that age-related oxidative modifications of TTR can contribute to the onset of the senile forms of the TTR amyloidoses.
MeSH Terms
- Age Factors
- Aging
- Amyloid
- Amyloidosis
- Benzothiazoles
- Cell Line
- Humans
- Myocytes, Cardiac
- Oxidation-Reduction
- Point Mutation
- Prealbumin
- Protein Carbonylation
- Protein Multimerization
- Protein Structure, Secondary
- Protein Structure, Tertiary
- Recombinant Proteins
- Resveratrol
- Stilbenes
- Thiazoles