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Common transthyretin-derived amyloid fibril structures in patients with hereditary ATTR amyloidosis.Nature Communications Nov 2023Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The...
Systemic ATTR amyloidosis is an increasingly important protein misfolding disease that is provoked by the formation of amyloid fibrils from transthyretin protein. The pathological and clinical disease manifestations and the number of pathogenic mutational changes in transthyretin are highly diverse, raising the question whether the different mutations may lead to different fibril morphologies. Using cryo-electron microscopy, however, we show here that the fibril structure is remarkably similar in patients that are affected by different mutations. Our data suggest that the circumstances under which these fibrils are formed and deposited inside the body - and not only the fibril morphology - are crucial for defining the phenotypic variability in many patients.
Topics: Humans; Amyloid; Amyloid Neuropathies, Familial; Cryoelectron Microscopy; Prealbumin; Proteostasis Deficiencies
PubMed: 37993462
DOI: 10.1038/s41467-023-43301-3 -
International Journal of Molecular... Nov 2020Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs)... (Review)
Review
Transthyretin (TTR), previously named prealbumin is a plasma protein secreted mainly by the liver and choroid plexus (CP) that is a carrier for thyroid hormones (THs) and retinol (vitamin A). The structure of TTR, with four monomers rich in β-chains in a globular tetrameric protein, accounts for the predisposition of the protein to aggregate in fibrils, leading to a rare and severe disease, namely transthyretin amyloidosis (ATTR). Much effort has been made and still is required to find new therapeutic compounds that can stabilize TTR ("kinetic stabilization") and prevent the amyloid genetic process. Moreover, TTR is an interesting therapeutic target for neurodegenerative diseases due to its recognized neuroprotective properties in the cognitive impairment context and interestingly in Alzheimer's disease (AD). Much evidence has been collected regarding the neuroprotective effects in AD, including through in vitro and in vivo studies as well as a wide range of clinical series. Despite this supported hypothesis of neuroprotection for TTR, the mechanisms are still not completely clear. The aim of this review is to highlight the most relevant findings on the neuroprotective role of TTR, and to summarize the recent progress on the development of TTR tetramer stabilizers.
Topics: Alzheimer Disease; Amyloid Neuropathies, Familial; Humans; Prealbumin; Protein Stability
PubMed: 33212973
DOI: 10.3390/ijms21228672 -
European Journal of Heart Failure Sep 2022
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Echocardiography; Heart Failure; Humans; Prealbumin
PubMed: 35906799
DOI: 10.1002/ejhf.2639 -
PloS One 2022Acute phase reactants (APRs) are proteins altered by inflammation and are regarded as surrogate markers representing inflammatory status. This study evaluated changes of...
OBJECTIVES
Acute phase reactants (APRs) are proteins altered by inflammation and are regarded as surrogate markers representing inflammatory status. This study evaluated changes of albumin (Alb), prealbumin (Palb), and ischemia-modified albumin (IMA) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in response to alterations in disease activity and the correlation between disease activity and Alb, Palb, and IMA.
METHODS
Fifty-nine patients with AAV registered in the prospective SHAVE cohort, who had available serial blood samples at least three months apart were included (indicated as pre and post). Correlation analysis and linear regression were carried out to determine the relationship between continuous variables. Alb, Palb, and IMA levels in 40 healthy controls (HCs) were compared with patients with AAV.
RESULTS
Comparison of Alb, Palb, and IMA levels in HCs and in patients at initial (pre) and follow-up (post) time points revealed that Alb levels significantly increased following the improvement of disease activity and were comparable between HCs and patients at follow-up (post). Meanwhile, there was no significant difference noted in Palb and IMA levels after the decrease of disease activity. While initial (pre) Alb and Palb were significantly associated with BVAS, a subgroup analysis of patients with new-onset disease showed Palb was no longer significantly associated with Birmingham Vasculitis Activity Score (BVAS). Multivariate linear regression showed Alb level (standardized β = -0.377; 95% confidence interval: -5.623, -1.260; p = 0.003) was an independent predictor of BVAS at baseline.
CONCLUSIONS
Among Alb, Palb, and IMA, we found that Alb could be a useful marker indicating disease activity in patients with AAV.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Humans; Prealbumin; Prospective Studies; Serum Albumin; Serum Albumin, Human
PubMed: 35797397
DOI: 10.1371/journal.pone.0271055 -
Cerebrovascular Diseases Extra 2022Prealbumin is a marker of malnutrition and inflammation. It has been associated with poor prognosis in cardiovascular disease, but less is known in stroke patients. Our...
INTRODUCTION
Prealbumin is a marker of malnutrition and inflammation. It has been associated with poor prognosis in cardiovascular disease, but less is known in stroke patients. Our objective was to evaluate the association of prealbumin levels at admission with prognosis in patients with stroke treated with mechanical thrombectomy.
METHODS
Retrospective study of a prospective database of consecutive patients treated with mechanical thrombectomy. Clinical, radiological, and blood parameters including serum prealbumin, and prognostic variables such as respiratory infection, in-hospital mortality, and the modified Rankin scale at 3 months were collected.
RESULTS
We included 319 patients between 2018 and 2019. Prealbumin levels were significantly lower in patients older than 80 years, women, patients with a prestroke Rankin score >2, a glomerular filtrate rate <60 mL/min, and in those with atrial fibrillation. Regarding prognostic variables, prealbumin levels were not associated with respiratory infection. Low prealbumin levels were associated with poor functional prognosis (Rankin score >2), in-hospital mortality, and 3-month mortality. In multivariate analysis, prealbumin was an independent risk factor associated with mortality at 3 months, OR 0.92 [0.86-0.98], p = 0.019.
CONCLUSION
Lower prealbumin levels at admission behaved as an independent predictor of long-term mortality in patients treated with mechanical thrombectomy. These results should be replicated in other cohorts.
Topics: Female; Humans; Brain Ischemia; Prealbumin; Prognosis; Retrospective Studies; Stroke; Thrombectomy; Treatment Outcome; Aged, 80 and over
PubMed: 36007497
DOI: 10.1159/000526354 -
Nature Reviews. Drug Discovery Nov 2015The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the... (Review)
Review
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure-activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.
Topics: Animals; Biological Factors; Humans; Neurodegenerative Diseases; Prealbumin; Protein Aggregation, Pathological; Protein Folding; Protein Transport; Structure-Activity Relationship; Treatment Outcome
PubMed: 26338154
DOI: 10.1038/nrd4593 -
European Journal of Heart Failure Sep 2022
Topics: Amyloid Neuropathies, Familial; Anticoagulants; Heart Failure; Humans; Prealbumin
PubMed: 35919942
DOI: 10.1002/ejhf.2648 -
JACC. Cardiovascular Imaging Dec 2016
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Heart; Humans; Prealbumin; Primary Dysautonomias
PubMed: 27838301
DOI: 10.1016/j.jcmg.2016.08.003 -
International Journal of Molecular... Dec 2022Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv...
Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv amyloidosis can present as a progressive, axonal sensory autonomic and motor neuropathy or as an infiltrative cardiomyopathy. The definition of biomarkers for the early diagnosis of ATTRv is particularly important in the current era of emerging treatments. In this sense, metabolomics could be an instrument able to provide metabolic profiles with their related metabolic pathways, and we would propose them as possible fluid biomarkers. The aim of this study is to identify altered metabolites (free fatty acids and amino acids) in subjects with a confirmed pathogenic variant. Out of the studied total free fatty acids and amino acids, the serum values of palmitic acid are significantly lower in the ATTRv patients compared to the recruited healthy subjects. The metabolic remodeling identified in this neurogenetic disorder could be the manifestation of pathophysiological processes of the disease, such as mitochondrial dysfunction and neuroinflammation, and contribute to explaining some of its clinical manifestations.
Topics: Humans; Pilot Projects; Fatty Acids, Nonesterified; Amyloid Neuropathies, Familial; Amyloidosis, Familial; Prealbumin
PubMed: 36555770
DOI: 10.3390/ijms232416133 -
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