ABSTRACT
Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the myocardial extracellular deposition of amyloid fibrils formed from the dissociation of TTR tetramer into monomers. The rate-limiting step in TTR amyloidogenesis is the dissociation of the TTR tetramer into monomers: Tafamidis is an effective TTR-stabilizer in its native homotetrameric structure. Tafamidis is a safe and effective drug in reducing symptoms, hospitalization and mortality in accurately selected patients affected by hereditary and wild-type transthyretin amyloid cardiomyopathy.
Subject(s)
Amyloid Neuropathies, Familial , Benzoxazoles , Cardiomyopathies , Humans , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Amyloid Neuropathies, Familial/drug therapy , Amyloid Neuropathies, Familial/complications , Amyloid Neuropathies, Familial/genetics , Cardiomyopathies/drug therapy , Cardiomyopathies/metabolism , Prealbumin/genetics , Prealbumin/metabolismABSTRACT
BACKGROUND: This research aims to increase our knowledge of amyloidoses. These disorders cause incorrect protein folding, affecting protein functionality (on structure). Fibrillar deposits are the basis of some wellknown diseases, such as Alzheimer, Creutzfeldt-Jakob diseases and type II diabetes. For many of these amyloid proteins, the relative precursors are known. Discovering new protein precursors involved in forming amyloid fibril deposits would improve understanding the pathological processes of amyloidoses. RESULTS: A new classifier, called ENTAIL, was developed using over than 4000 molecular descriptors. ENTAIL was based on the Naive Bayes Classifier with Unbounded Support and Gaussian Kernel Type, with an accuracy on the test set of 81.80%, SN of 100%, SP of 63.63% and an MCC of 0.683 on a balanced dataset. CONCLUSIONS: The analysis carried out has demonstrated how, despite the various configurations of the tests, performances are superior in terms of performance on a balanced dataset.
Subject(s)
Amyloidosis , Diabetes Mellitus, Type 2 , Humans , Amyloid , Bayes Theorem , Protein FoldingABSTRACT
Amyloidoses are a group of diseases associated with the formation of pathological protein fibrils with cross-ß structures. Approximately 5-10% of the cases of these diseases are determined by amyloidogenic mutations, as well as by transmission of infectious amyloids (prions) between organisms. The most common group of so-called sporadic amyloidoses is associated with abnormal aggregation of wild-type proteins. Some sporadic amyloidoses are known to be induced only against the background of certain pathologies, but in some cases the cause of amyloidosis is unclear. It is assumed that these diseases often occur by accident. Here we present facts and hypotheses about the association of sporadic amyloidoses with vascular pathologies, trauma, oxidative stress, cancer, metabolic diseases, chronic infections and COVID-19. Generalization of current data shows that all sporadic amyloidoses can be regarded as a secondary event occurring against the background of diseases provoking a cellular stress response. Various factors causing the stress response provoke protein overproduction, a local increase in the concentration or modifications, which contributes to amyloidogenesis. Progress in the treatment of vascular, metabolic and infectious diseases, as well as cancers, should lead to a significant reduction in the risk of sporadic amyloidoses.
Subject(s)
Amyloidosis/etiology , Stress, Physiological , Brain Injuries/complications , Communicable Diseases/complications , Humans , Metabolic Diseases/complications , Neoplasms/complications , Oxidative Stress , Vascular Diseases/complicationsABSTRACT
Many types of amyloidoses are pathologically characterized by the deposition of amyloid, which is comprised of fibrils formed by abnormally aggregated proteins, in various peripheral tissues and the central nervous system (CNS). Neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are well-known CNS amyloidoses that are characterized by amyloid deposition both inside and outside of cells. The amyloidogenic proteins of each disease have distinct primary sequences, and they normally function as soluble proteins. However, these proteins all aggregate and form amyloid with a common intermolecular tertiary structure, namely, a cross-ß-sheet structure, finally leading to the onset of each disease. Therefore, inhibition of the aggregation of amyloid proteins or efficient clearance of the already formed amyloids are thought to be promising therapeutic strategies against amyloidoses.
Subject(s)
Alzheimer Disease , Amyloidosis , Frontotemporal Dementia , Parkinson Disease , Amyloid , Amyloidosis/therapy , HumansABSTRACT
Primary localized cutaneous amyloidosis (PLCA) is a recalcitrant sporadic dermatological condition and most treatments have failed so far. We studied the efficacy of topical dimethyl sulfoxide (DMSO) 50% solution in comparison with tretinoin 0.5% cream in treatment of macular amyloidosis. In this split-side within-person single-blinded randomized clinical trial, 18 patients with bilateral macular amyloidosis received topical DMSO 50% solution and tretinoin 0.5% cream either on their right or the left side. The colorimetry, pruritus scoring, and photography were done. A significant pigmentation decline per each follow-up was observed in DMSO group compared to the tretinoin group (tretinoin: -1.31 vs DMSO: -7.34; difference in slopes: -6.03 [95% confidence interval: -12.06 to -0.01], PInteraction = .049). An insignificant diminution trend in pigmentation was observed for both treatments (Ptretinoin = .672, PDMSO = .092). Also, both treatments relived itchiness, but DMSO completely dispatched itchiness from the first follow-up (P = .003 for tretinoin and <.0001 for DMSO). In conclusion, our results showed DMSO and tretinoin cream have the positive effect on the both pigmentation and itchiness in PLCA. DMSO may be more beneficial than tretinoin, since DMSO was significantly better in reducing itchiness. More investigations are warranted to provide sufficient evidence.
Subject(s)
Amyloidosis, Familial , Skin Diseases, Genetic , Administration, Topical , Dimethyl Sulfoxide/adverse effects , Humans , Tretinoin/adverse effectsABSTRACT
Numerous proteins can coalesce into amyloid self-assemblies, which are responsible for a class of diseases called amyloidoses, but which can also fulfill important biological functions and are of great interest for biotechnology. Amyloid aggregation is a complex multi-step process, poorly prone to detailed structural studies. Therefore, small molecules interacting with amyloids are often used as tools to probe the amyloid aggregation pathway and in some cases to treat amyloidoses as they prevent pathogenic protein aggregation. Here, we report on SynAggreg, an in vitro high-throughput (HT) platform dedicated to the precision study of amyloid aggregation and the effect of modulator compounds. SynAggreg relies on an accurate bi-fluorescent amyloid-tracer readout that overcomes some limitations of existing HT methods. It allows addressing diverse aspects of aggregation modulation that are critical for pathomechanistic studies, such as the specificity of compounds toward various amyloids and their effects on aggregation kinetics, as well as the co-assembly propensity of distinct amyloids and the influence of prion-like seeding on self-assembly. Furthermore, SynAggreg is the first HT technology that integrates tailored methodology to systematically identify synergistic compound combinations-an emerging strategy to improve fatal amyloidoses by targeting multiple steps of the aggregation pathway. To this end, we apply analytical combinatorial scores to rank the inhibition efficiency of couples of compounds and to readily detect synergism. Finally, the SynAggreg platform should be suited for the characterization of a broad class of amyloids, whether of interest for drug development purposes, for fundamental research on amyloid functions, or for biotechnological applications.
Subject(s)
Amyloidogenic Proteins/chemistry , High-Throughput Screening Assays/methods , Small Molecule Libraries/pharmacology , Amyloidogenic Proteins/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Drug Synergism , Humans , KineticsABSTRACT
AIM: Gadolinium-based nanoparticles were functionalized with either the Pittsburgh compound B or a nanobody (B10AP) in order to create multimodal tools for an early diagnosis of amyloidoses. MATERIALS & METHODS: The ability of the functionalized nanoparticles to target amyloid fibrils made of ß-amyloid peptide, amylin or Val30Met-mutated transthyretin formed in vitro or from pathological tissues was investigated by a range of spectroscopic and biophysics techniques including fluorescence microscopy. RESULTS: Nanoparticles functionalized by both probes efficiently interacted with the three types of amyloid fibrils, with KD values in 10 micromolar and 10 nanomolar range for, respectively, Pittsburgh compound B and B10AP nanoparticles. Moreover, they allowed the detection of amyloid deposits on pathological tissues. CONCLUSION: Such functionalized nanoparticles could represent promising flexible and multimodal imaging tools for the early diagnostic of amyloid diseases, in other words, Alzheimer's disease, Type 2 diabetes mellitus and the familial amyloidotic polyneuropathy.
Subject(s)
Aniline Compounds/chemistry , Gadolinium/chemistry , Nanoparticles/chemistry , Plaque, Amyloid/diagnosis , Single-Domain Antibodies/chemistry , Thiazoles/chemistry , Alzheimer Disease/diagnosis , Amyloid beta-Peptides/analysis , Animals , Brain/pathology , Diabetes Mellitus, Type 2/diagnosis , Humans , Immunohistochemistry , Islet Amyloid Polypeptide/analysis , Mice , Multimodal ImagingABSTRACT
Amyloidomas are rare tumor-like depositions of abnormally folded, insoluble proteins that may be seen in the setting of systemic amyloidosis or as isolated tumoral deposits. Focal, isolated amyloidomas carry an excellent prognosis whereas systemic amyloidoses do not. The ability to identify or suggest amyloidoma on imaging studies may help direct laboratory testing and eventual diagnosis. Amyloidomas involving the head and neck have been variably described from homogeneously T2 hypointense to iso-slightly hyperintense relative to skeletal muscle. Herein we present two patients with pharyngeal submucosal amyloidomas of differing sizes and imaging characteristics to emphasize their potential widely variable imaging appearance and broaden our knowledge of these rare lesions.
Subject(s)
Amyloidosis/diagnostic imaging , Pharyngeal Diseases/diagnostic imaging , Biopsy , Contrast Media , Diagnosis, Differential , Female , Fluorodeoxyglucose F18 , Humans , Magnetic Resonance Imaging , Middle Aged , Positron Emission Tomography Computed Tomography , Radiopharmaceuticals , Tomography, X-Ray ComputedABSTRACT
Preeclampsia (PE) is a complex, multisystem disorder that remains a leading cause of morbidity and mortality in pregnancy. Four main classes of dysregulation accompany PE and are widely considered to contribute to its severity. These are abnormal trophoblast invasion of the placenta, anti-angiogenic responses, oxidative stress, and inflammation. What is lacking, however, is an explanation of how these themselves are caused. We here develop the unifying idea, and the considerable evidence for it, that the originating cause of PE (and of the four classes of dysregulation) is, in fact, microbial infection, that most such microbes are dormant and hence resist detection by conventional (replication-dependent) microbiology, and that by occasional resuscitation and growth it is they that are responsible for all the observable sequelae, including the continuing, chronic inflammation. In particular, bacterial products such as lipopolysaccharide (LPS), also known as endotoxin, are well known as highly inflammagenic and stimulate an innate (and possibly trained) immune response that exacerbates the inflammation further. The known need of microbes for free iron can explain the iron dysregulation that accompanies PE. We describe the main routes of infection (gut, oral, and urinary tract infection) and the regularly observed presence of microbes in placental and other tissues in PE. Every known proteomic biomarker of "preeclampsia" that we assessed has, in fact, also been shown to be raised in response to infection. An infectious component to PE fulfills the Bradford Hill criteria for ascribing a disease to an environmental cause and suggests a number of treatments, some of which have, in fact, been shown to be successful. PE was classically referred to as endotoxemia or toxemia of pregnancy, and it is ironic that it seems that LPS and other microbial endotoxins really are involved. Overall, the recognition of an infectious component in the etiology of PE mirrors that for ulcers and other diseases that were previously considered to lack one.
ABSTRACT
Aggregation of globular proteins is an intractable problem which generally originates from partially folded structures. The partially folded structures first collapse non-specifically and then reorganize into amyloid-like fibrils via one or more oligomeric intermediates. The fibrils and their on/off pathway intermediates may be toxic to cells and form toxic deposits in different human organs. To understand the basis of origins of the aggregation diseases, it is vital to study in details the conformational properties of the amyloidogenic partially folded structures of the protein. In this work, we examined the effects of ofloxacin, a synthetic fluoroquinolone compound on the fibrillar aggregation of hen egg-white lysozyme. Using two aggregation conditions (4M GuHCl at pH 7.0 and 37 °C; and pH 1.7 at 65 °C) and a number of biophysical techniques, we illustrate that ofloxacin accelerates fibril formation of lysozyme by binding to partially folded structures and modulating their secondary, tertiary structures and surface hydrophobicity. We also demonstrate that Ofloxacin-induced fibrils show polymorphism of morphology, tinctorial properties and hydrophobic surface exposure. This study will assist in understanding the determinant of fibril formation and it also indicates that caution should be exercised in the use of ofloxacin in patients susceptible to various aggregation diseases.
Subject(s)
Amyloid/chemistry , Amyloid/ultrastructure , Molecular Docking Simulation , Muramidase/chemistry , Muramidase/ultrastructure , Ofloxacin/chemistry , Binding Sites , Crystallization , Enzyme Activation , Hydrophobic and Hydrophilic Interactions , Protein Aggregates , Protein Binding , Protein ConformationABSTRACT
The extracellular aggregation of proteins into proteotoxic oligomers and amyloid fibrils is implicated in the onset and pathology of numerous diseases referred to as amyloid diseases. All of the proteins that aggregate extracellularly in association with amyloid disease pathogenesis originate in the endoplasmic reticulum (ER) and are secreted through the secretory pathway. Disruptions in ER protein homeostasis or proteostasis (i.e., ER stress) can facilitate the aberrant secretion of misfolded protein conformations to the extracellular space and exacerbate pathologic protein aggregation into proteotoxic species. Activation of an ER stress-responsive signaling pathway, the Unfolded Protein Response (UPR), restores ER proteostasis through the transcriptional regulation of ER proteostasis pathways. In contrast, the functional role for the UPR in regulating extracellular proteostasis during ER stress is poorly defined. We recently identified ERdj3 as a UPR-regulated secreted chaperone that increases extracellular proteostasis capacity in response to ER stress, revealing a previously-unanticipated direct mechanism by which the UPR impacts extracellular proteostasis. Here, we discuss the functional implications of ERdj3 secretion on extracellular proteostasis maintenance and define the mechanisms by which ERdj3 secretion coordinates intra- and extracellular proteostasis environments during ER stress.
Subject(s)
Extracellular Space/metabolism , Unfolded Protein Response , Animals , Endoplasmic Reticulum Stress , HSP40 Heat-Shock Proteins/metabolism , Humans , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Models, Biological , Molecular Chaperones/metabolism , Protein ConformationABSTRACT
The deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease, Parkinson's disease, prion diseases and type II diabetes. These disorders, referred to as amyloidoses, generally become apparent late in life. Their psycho-sociological and economic incidence in western societies will be therefore considerable in the coming decades due to the ageing of the population. Neither preventing nor curative treatments are available yet. These disorders constitute therefore a medical challenge of great importance. Thus, an extensive research is being carried out to understand, at the molecular level, (i) how amyloidogenic proteins misfold and convert from their soluble form into amyloid fibrils, and (ii) how these aggregates or some of their oligomeric precursor species are toxic. The formation of amyloid fibrils proceeds through a complex nucleation/polymerisation mechanism with the formation of various species, including small oligomers. In this review, we focus on how VHHs or nanobodies, the antigen-binding domains of camelid heavy-chain antibodies, are being increasingly used to characterise each of the species formed on the pathway of fibril formation in terms of structure, stability, kinetics of formation and toxicity. We first introduce the characteristic features of nanobodies compared to those of conventional antibody fragments. Thereafter, we discuss how nanobodies, due to their unique properties, are used as probes to dissect the molecular mechanisms of misfolding and aggregation of six proteins associated with diseases, i.e. human lysozyme, ß2-microglobulin, α-synuclein, prion, polyadenylate binding protein nuclear 1 and amyloid ß-peptide. A brief general presentation of each disease and the associated peptide/protein is also provided. In addition, we discuss how nanobodies could be used as early diagnostic tools and as novel strategies to treat diseases associated with protein misfolding and aggregation.
Subject(s)
Camelids, New World/immunology , Immunoglobulin Heavy Chains/therapeutic use , Protein Aggregation, Pathological/drug therapy , Proteostasis Deficiencies/drug therapy , Single-Domain Antibodies/therapeutic use , Animals , Camelids, New World/genetics , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Protein Aggregation, Pathological/immunology , Proteostasis Deficiencies/immunology , Single-Domain Antibodies/genetics , Single-Domain Antibodies/immunologyABSTRACT
Amyloidosis is a rare disorder in which insoluble amyloid proteins are deposited in body organs, causing abnormal protein build-up in tissues and eventually leading to organ dysfunction and death. It affects less than 200,000 people in the United States, classifying it as a rare disease according to the National Institutes of Health. Definitive determination of the underlying protein is critical since prognosis and treatment of amyloidosis can vary widely depending on the responsible protein. The following paper describes the various types and clinical features of amyloidosis and provides an overview of current diagnostic tools and therapies.