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Biophysical Chemistry Dec 2013High hydrostatic pressure (HHP) is a valuable tool to study processes such as protein folding, protein hydration and protein-protein interactions. HHP is a... (Review)
Review
High hydrostatic pressure (HHP) is a valuable tool to study processes such as protein folding, protein hydration and protein-protein interactions. HHP is a nondestructive technique because it reversibly affects internal cavities excluded from the solvent present in the hydrophobic core of proteins. HHP allows the solvation of buried amino acid side chains, thus shifting the equilibrium towards states of the studied molecule or molecular ensemble that occupy smaller volumes. HHP has long been used to dissociate multimeric proteins and protein aggregates and allows investigation of intermediate folding states, some of which are formed by proteins involved in human degenerative diseases, such as spongiform encephalopathies and Parkinson's disease, as well as cancer. When coupled with nuclear magnetic resonance and spectroscopic methods such as infrared and fluorescence spectroscopy, HHP treatment facilitates the understanding of protein folding and misfolding processes; the latter is related to protein aggregation into amyloid or amorphous species. In this review, we will address how HHP provides information about intermediate folding states and the aggregation processes of p53, which is related to cancer, and prion proteins, transthyretin and α-synuclein, which are related to human degenerative diseases.
Topics: Amyloid; Animals; Humans; Hydrostatic Pressure; Neoplasms; Neurodegenerative Diseases; Nuclear Magnetic Resonance, Biomolecular; Prealbumin; Prions; Protein Binding; Protein Conformation; Protein Folding; Protein Structure, Quaternary; Thermodynamics; Tumor Suppressor Protein p53; alpha-Synuclein
PubMed: 23849959
DOI: 10.1016/j.bpc.2013.06.002 -
Orphanet Journal of Rare Diseases May 2024There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers....
BACKGROUND
There are novel medications approved for the treatment of hereditary transthyretin amyloidosis (ATTRv), classified as transthyretin (TTR) stabilizers or gene silencers. While many patients may be on both classes of medications, there is no data available on the safety and efficacy of combination therapy.
OBJECTIVES
To describe ATTRv patient and TTR-targeted therapy characteristics in a US cohort, and compare outcomes with combination therapy versus monotherapy.
METHODS
We performed a retrospective cohort study with electronic health record data of patients with ATTRv seen at a single institution between January 2018 and December 2022. We collected data on symptomatology, gene mutation, disease severity, ATTRv treatment, hospitalizations, and mortality.
RESULTS
One hundred sixty-two patients with ATTRv were identified. The average age at diagnosis was 65 years. 86 patients (53%) had the V122I variant. 119 patients were symptomatic, of whom 103 were started on ATTRv-specific treatment. 41 patients (40%) had cardiomyopathy only, and 53 (51%) had a mixed phenotype of cardiomyopathy and neuropathy. 38 patients (37%) received therapy with both a gene silencer and protein stabilizer. 9 patients (15%) in the monotherapy group had two or more cardiac hospitalizations after starting treatment, compared to 3 patients (9%) on combination therapy (p=0.26). The adjusted hazard ratio of all-cause mortality for the patients on combination therapy compared to monotherapy was 0.37 (0.08-1.8, p=0.21).
CONCLUSIONS
While the efficacy is unproven, over one-third of patients with ATTRv are on both a stabilizer and a silencer. There were no safety issues for combination therapy. There was a trend towards improved hospitalizations and survival in patients in the combination group but this was not statistically significant. Larger studies with longer follow-up are necessary to determine benefit of combination therapy.
Topics: Humans; Amyloid Neuropathies, Familial; Male; Female; Retrospective Studies; Aged; Middle Aged; Cohort Studies; Prealbumin; Aged, 80 and over; Adult
PubMed: 38720335
DOI: 10.1186/s13023-024-03198-7 -
European Journal of Heart Failure May 2023Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference...
AIMS
Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study.
METHODS AND RESULTS
Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14 ml. At 9 months, the least-squares mean change in SV was -0.3 ± 1.2 ml for patisiran and -5.4 ± 1.9 ml for placebo (p = 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3 ml for patisiran and - 8.1 ± 2.3 ml for placebo (p = 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran.
CONCLUSIONS
Patisiran may delay progression of LV chamber dysfunction starting at 9 months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.
Topics: Humans; Stroke Volume; Prealbumin; Heart Failure; Amyloid Neuropathies, Familial
PubMed: 36693807
DOI: 10.1002/ejhf.2783 -
Journal of the American Heart... Feb 2024Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing...
BACKGROUND
Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive and ultimately fatal cardiomyopathy. Biomarkers reflecting multiorgan dysfunction are of increasing importance in patients with heart failure; however, their significance in ATTR-CA remains largely unknown. The aims of this study were to characterize the multifaceted nature of ATTR-CA using blood biomarkers and assess the association between blood biomarkers and prognosis.
METHODS AND RESULTS
This is a retrospective cohort study of 2566 consecutive patients diagnosed with ATTR-CA between 2007 and 2023. Anemia (39%), high urea (52%), hyperbilirubinemia (18%), increased alkaline phosphatase (16%), increased CRP (C-reactive protein; 27%), and increased troponin (98.2%) were common findings in the overall population, whereas hyponatremia (6%) and hypoalbuminemia (2%) were less common. These abnormalities were most common in patients with p.(V142I) hereditary ATTR-CA, and became more prevalent as the severity of cardiac disease increased. Multivariable Cox regression analysis demonstrated that anemia (hazard ratio [HR], 1.19 [95% CI, 1.04-1.37]; =0.01), high urea (HR, 1.23 [95% CI, 1.04-1.45]; =0.01), hyperbilirubinemia (HR, 1.32 [95% CI, 1.13-1.57; =0.001), increased alkaline phosphatase (HR, 1.20 [95% CI, 1.01-1.42; =0.04), hyponatremia (HR, 1.65 [95% CI, 1.28-2.11]; <0.001), and troponin-T >56 ng/L (HR, 1.72 [95% CI, 1.46-2.03]; <0.001) were all independently associated with mortality in the overall population. The association between biomarkers and mortality varied across the spectrum of genotypes and left ventricular ejection fraction, with anemia remining independently associated with mortality in p.(V142I) hereditary ATTR-CA (HR, 1.58 [95% CI, 1.17-2.12]; =0.003) and in a subgroup of the overall population with a left ventricular ejection fraction ≤40% (HR, 1.39 [95% CI, 1.08-1.81]; =0.01).
CONCLUSIONS
Cardiac and noncardiac biomarker abnormalities were common and reflect the complex and multifaceted nature of ATTR-CA, with a wide range of biomarkers remaining independently associated with mortality. Clinical trials are needed to investigate whether biomarker abnormalities represent modifiable risk factors that if specifically targeted could improve outcomes.
Topics: Humans; Prealbumin; Cardiomyopathies; Amyloid Neuropathies, Familial; Stroke Volume; Retrospective Studies; Alkaline Phosphatase; Hyponatremia; Ventricular Function, Left; Prognosis; Biomarkers; Anemia; Hyperbilirubinemia; Urea
PubMed: 38314569
DOI: 10.1161/JAHA.123.033094 -
The FEBS Journal Oct 2009Thyroid hormones are involved in growth and development, particularly of the brain. Thus, it is imperative that these hormones get from their site of synthesis to their... (Review)
Review
Thyroid hormones are involved in growth and development, particularly of the brain. Thus, it is imperative that these hormones get from their site of synthesis to their sites of action throughout the body and the brain. This role is fulfilled by thyroid hormone distributor proteins. Of particular interest is transthyretin, which in mammals is synthesized in the liver, choroid plexus, meninges, retinal and ciliary pigment epithelia, visceral yolk sac, placenta, pancreas and intestines, whereas the other thyroid hormone distributor proteins are synthesized only in the liver. Transthyretin is synthesized by all classes of vertebrates; however, the tissue specificity of transthyretin gene expression varies widely between classes. This review summarizes what is currently known about the evolution of transthyretin synthesis in vertebrates and presents hypotheses regarding tissue-specific synthesis of transthyretin in each vertebrate class.
Topics: Acute-Phase Reaction; Animals; Brain; Carrier Proteins; Evolution, Molecular; Female; Gene Expression; Humans; Ligands; Male; Membrane Proteins; Models, Biological; Prealbumin; Pregnancy; Retinol-Binding Proteins; Thyroid Hormones; Tissue Distribution; Vertebrates; Thyroid Hormone-Binding Proteins
PubMed: 19725882
DOI: 10.1111/j.1742-4658.2009.07244.x -
The Neurologist Sep 2021Leptomeningeal amyloidosis (LA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal... (Review)
Review
INTRODUCTION
Leptomeningeal amyloidosis (LA) represents a rare subtype of familial transthyretin (TTR) amyloidosis, characterized by deposition of amyloid in cranial and spinal leptomeninges. Of >120 TTR mutations identified, few have been associated with LA.
CASE REPORT
A 27-year-old male presented with a 2-year history of progressive symptoms including cognitive decline and right-sided weakness and numbness. Cerebrospinal fluid (CSF) analyses demonstrated high protein level. Gadolinium-enhanced magnetic resonance imaging (MRI) revealed extensive leptomeningeal enhancement over the surface of the brain and spinal cord. Pathologic analyses revealed a TTR mutation c.113A>G (p.D38G).
REVIEW SUMMARY
Fifteen mutations and genotype-phenotype correlation of 72 LA patients have been summarized to provide an overview of LA associated with transthyretin mutations. The mean age of clinical onset was 44.9 years and the neurological symptoms primarily included cognitive impairment, headache, ataxia seizures and hearing, visual loss. CSF analysis showed elevated high CSF protein level and MRI revealed extensive leptomeningeal enhancement.
CONCLUSION
Clinicians should be aware of this rare form of familial transthyretin amyloidosis as well as its typical MRI enhancement and high CSF protein. The important role of biopsy, genetic testing and the potential early diagnosis value of contrast MRI were suggested. Early recognition of these characteristics is important to provide misdiagnosis and shorten the time before correct diagnosis. These findings expand the phenotypic spectrum of TTR gene and have implications for the diagnosis, treatment, and systematic study of LA.
Topics: Adult; Amyloidosis; Humans; Magnetic Resonance Imaging; Male; Meninges; Mutation; Prealbumin
PubMed: 34491937
DOI: 10.1097/NRL.0000000000000337 -
Internal Medicine (Tokyo, Japan) Jan 2021Cardiac involvement of systemic amyloidosis is preferentially observed in patients with amyloid light chain amyloidosis or transthyretin amyloidosis (ATTR). Owing to the... (Review)
Review
Cardiac involvement of systemic amyloidosis is preferentially observed in patients with amyloid light chain amyloidosis or transthyretin amyloidosis (ATTR). Owing to the development of diagnostic modalities and changes in recognition by physicians, transthyretin cardiac amyloidosis (ATTR-CA) is now understood to be a more common cause of heart failure than previously thought. Recent progress in disease-modifying therapeutic interventions, such as transthyretin stabilizers, has resulted in ATTR-CA changing from an incurable disease to a curable disease. These interventions are particularly effective in patients with mild symptoms of heart failure, thus indicating that early detection and a precise diagnosis are important for improving the prognosis. In this review article, we summarize the recent reports of early screening of ATTR-CA and describe some important points regarding the making of a precise diagnosis, especially focusing on histological evaluations.
Topics: Amyloid Neuropathies, Familial; Early Diagnosis; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Prealbumin
PubMed: 32713926
DOI: 10.2169/internalmedicine.5505-20 -
European Journal of Heart Failure Jun 2023
Topics: Humans; Prealbumin; Heart Failure; Critical Pathways; Amyloid Neuropathies, Familial; Early Diagnosis; Cardiomyopathies
PubMed: 37191114
DOI: 10.1002/ejhf.2890 -
Open Biology Sep 2015Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired...
Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR-ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.
Topics: Animals; Binding Sites; Cross-Linking Reagents; Humans; Ligands; Mice; Mice, Inbred C57BL; Models, Molecular; Piperidines; Prealbumin; Protein Structure, Quaternary; Thyroxine
PubMed: 26400472
DOI: 10.1098/rsob.150105 -
International Journal of Molecular... Mar 2020Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid,... (Review)
Review
Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer's disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Drug Delivery Systems; Drug Discovery; Humans; Prealbumin
PubMed: 32197355
DOI: 10.3390/ijms21062075