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Marques N, Aguiar Rosa S, Cordeiro F, Menezes Fernandes R, Ferreira C, Bento D, Brito D, Cardim N, Lopes L, Azevedo O. Portuguese recommendations for the management of transthyretin amyloid cardiomyopathy (Part 1 of 2): Screening, diagnosis and treatment. Developed by the Task Force on the management of transthyretin amyloid cardiomyopathy of the Working Group on Myocardial and Pericardial Diseases of the Portuguese Society of Cardiology. Rev Port Cardiol 2025; 44 Suppl 1:7-48. [PMID: 39956765 DOI: 10.1016/j.repc.2024.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 11/19/2024] [Indexed: 02/18/2025] Open
Affiliation(s)
- Nuno Marques
- Cardiology Department, Unidade Local de Saúde do Alentejo Central, Portugal; Faculdade de Medicina e Ciências Biomédicas, Universidade do Algarve, Portugal; ABC-RI - Algarve Biomedical Center Research Institute, Portugal; Active Ageing Competence Center, Portugal.
| | - Sílvia Aguiar Rosa
- Cardiology Department, Hospital de Santa Marta, Unidade Local de Saúde São José, Lisboa, Portugal; Centro Clínico Académico de Lisboa, Lisboa, Portugal; Nova Medical School, Lisboa, Portugal
| | - Filipa Cordeiro
- Cardiology Department, Hospital Senhora da Oliveira, Guimarães, Portugal
| | | | - Catarina Ferreira
- Cardiology Department, Hospital de S. Pedro, Unidade Local de Saúde de Trás-os-Montes e Alto Douro, Vila Real, Portugal
| | - Dina Bento
- Cardiology Department, Hospital de Faro, Unidade Local de Saúde do Algarve, Portugal
| | - Dulce Brito
- Cardiology Department, Hospital de Santa Maria, Lisboa, Portugal; CCUL@RISE, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Nuno Cardim
- Cardiology Department, Hospital CUF-Descobertas, Lisbon, Portugal; Nova Medical School, Lisboa, Portugal
| | - Luís Lopes
- Institute of Cardiovascular Science, University College London, UK; St Bartholomew's Hospital, Barts Heart Centre, London, UK
| | - Olga Azevedo
- Cardiology Department, Hospital Senhora da Oliveira, Guimarães, Portugal
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2
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Eze FN. Transthyretin Amyloidosis: Role of oxidative stress and the beneficial implications of antioxidants and nutraceutical supplementation. Neurochem Int 2024; 179:105837. [PMID: 39154837 DOI: 10.1016/j.neuint.2024.105837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Revised: 06/28/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Transthyretin (ATTR) amyloidosis constitutes a spectrum of debilitating neurodegenerative diseases instigated by systemic extracellular deposition of partially unfolded/aggregated aberrant transthyretin. The homotetrameric protein, TTR, is abundant in the plasma, and to a lesser extent the cerebrospinal fluid. Rate-limiting tetramer dissociation of the native protein is regarded as the critical step in the formation of morphologically heterogenous toxic aggregates and the onset of clinical manifestations such as polyneuropathy, cardiomyopathy, disturbances in motor and autonomic functions. Over the past few decades there has been increasing evidence suggesting that in addition to destabilization in TTR tetramer structure, oxidative stress may also play an important role in the pathogenesis of ATTR amyloidosis. In this review, an update on the impact of oxidative stress in TTR amyloidogenesis as well as TTR aggregate-mediated pathologies is discussed. The counteracting effects of antioxidants and nutraceutical agents explored in the treatment of ATTR amyloidosis based on recent evidence is also critically examined. The insights unveiled could further strengthen current understanding of the mechanisms underlying ATTR amyloidosis as well as extend the range of strategies for effective management of ATTR amyloidoses.
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Affiliation(s)
- Fredrick Nwude Eze
- Office of Research Administration, Chiang Mai University, Chiang Mai, 50200, Thailand; Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand.
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Redzepi B, Kamani CH, Maurizi N, Théaudin M, Prior J, Monney P. False Negative 99mTc-DPD Scintigraphy in pVal50Met (Val30Met) Hereditary Transthyretin Amyloidosis. CJC Open 2024; 6:118-121. [PMID: 38585682 PMCID: PMC10994964 DOI: 10.1016/j.cjco.2023.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/09/2023] [Indexed: 04/09/2024] Open
Affiliation(s)
- Betim Redzepi
- Department of Cardiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Christel H. Kamani
- Department of Cardiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Niccolo Maurizi
- Department of Cardiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Marie Théaudin
- Department of Neurology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- University of Lausanne (UNIL), Faculty of Biology and Medicine, Lausanne, Switzerland
| | - John Prior
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- University of Lausanne (UNIL), Faculty of Biology and Medicine, Lausanne, Switzerland
| | - Pierre Monney
- Department of Cardiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- University of Lausanne (UNIL), Faculty of Biology and Medicine, Lausanne, Switzerland
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4
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Poli L, Labella B, Cotti Piccinelli S, Caria F, Risi B, Damioli S, Padovani A, Filosto M. Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy. Front Neurol 2023; 14:1242815. [PMID: 37869146 PMCID: PMC10585157 DOI: 10.3389/fneur.2023.1242815] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/11/2023] [Indexed: 10/24/2023] Open
Abstract
Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called "amyloid". The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.
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Affiliation(s)
- Loris Poli
- Unit of Neurology, Azienda Socio-Sanitaria Territoriale Spedali Civili, Brescia, Italy
| | - Beatrice Labella
- Unit of Neurology, Azienda Socio-Sanitaria Territoriale Spedali Civili, Brescia, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Stefano Cotti Piccinelli
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
| | - Filomena Caria
- NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
| | - Barbara Risi
- NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
| | - Simona Damioli
- NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
| | - Alessandro Padovani
- Unit of Neurology, Azienda Socio-Sanitaria Territoriale Spedali Civili, Brescia, Italy
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Massimiliano Filosto
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy
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5
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Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci 2022; 43:595-604. [PMID: 33188616 PMCID: PMC9780126 DOI: 10.1007/s10072-020-04889-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/05/2020] [Indexed: 01/12/2023]
Abstract
Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis is a rare autosomal dominantly inherited disorder caused by mutations in the transthyretin (TTR) gene. The pathogenetic model of ATTRv amyloidosis indicates that amyloidogenic, usually missense, mutations destabilize the native TTR favouring the dissociation of the tetramer into partially unfolded species that self-assemble into amyloid fibrils. Amyloid deposits and monomer-oligomer toxicity are the basis of multisystemic ATTRv clinical involvement. Peripheral nervous system (autonomic and somatic) and heart are the most affected sites. In the last decades, a better knowledge of pathomechanisms underlying the disease led to develop novel and promising drugs that are rapidly changing the natural history of ATTRv amyloidosis. Thus, clinicians face the challenge of timely diagnosis for addressing patients to appropriate treatment. As well, the progressive nature of ATTRv raises the issue of presymptomatic testing and risk management of carriers. The main aim of this review was to focus on what we know about ATTRv so far, from pathogenesis to clinical manifestations, diagnosis and hence patient's monitoring and treatment, and from presymptomatic testing to management of carriers.
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Affiliation(s)
- Fiore Manganelli
- Department of Neurosciences, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Via S. Pansini, 5, 80131, Naples, Italy.
| | - Gian Maria Fabrizi
- Section of Neurology, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
| | - Marco Luigetti
- Fondazione Policlinico Universitario A. Gemelli. UOC Neurologia, Rome, Italy
- Dipartimento di Neuroscienze, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paola Mandich
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI), University of Genoa, Genova, Italy
- IRCCS Policlinico San Martino, Genoa, Italy
| | - Anna Mazzeo
- Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Davide Pareyson
- Rare Neurodegenerative and Neurometabolic Diseases Unit, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
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6
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Current Understanding of Systemic Amyloidosis and Underlying Disease Mechanisms. Am J Cardiol 2022; 185 Suppl 1:S2-S10. [PMID: 36549788 DOI: 10.1016/j.amjcard.2022.10.057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 12/24/2022]
Abstract
Amyloidosis is a group of diverse disorders caused by misfolded proteins that aggregate into insoluble fibrils and ultimately cause organ damage. In medical practice, amyloidosis classification is based on the amyloid precursor protein type, of which amyloid immunoglobulin light chain, amyloid transthyretin, amyloid leukocyte chemotactic factor 2, and amyloid derived from serum amyloid A protein are the most common. Distinct mechanisms appear to be predominantly operational in the pathogenesis of particular types of amyloidosis, including increased protein precursor synthesis, somatic or germ line mutations, and inherent instability in the precursor protein in its wild form. An increased supply of misfolded proteins and/or a decreased capacity of the protein quality control systems can result in an imbalance that leads to increased circulation of misfolded proteins. Although the detection of mature fibrils is the basis for diagnosis of amyloidosis, a growing body of evidence has implicated the prefibrillar species as proteotoxic and key contributors to the development of the disease.
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7
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In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis. Int J Mol Sci 2021; 22:ijms22179488. [PMID: 34502397 PMCID: PMC8430710 DOI: 10.3390/ijms22179488] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/26/2021] [Accepted: 08/28/2021] [Indexed: 12/14/2022] Open
Abstract
Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.
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8
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Tozza S, Severi D, Spina E, Iovino A, Aruta F, Ruggiero L, Dubbioso R, Iodice R, Nolano M, Manganelli F. The neuropathy in hereditary transthyretin amyloidosis: A narrative review. J Peripher Nerv Syst 2021; 26:155-159. [PMID: 33960565 PMCID: PMC8360044 DOI: 10.1111/jns.12451] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/26/2021] [Accepted: 05/01/2021] [Indexed: 01/10/2023]
Abstract
Hereditary transthyretin amyloidosis (ATTRv) is a condition with adult onset, caused by mutation of the transthyretin (TTR) gene and characterized by extracellular deposition of amyloid fibrils in tissue, especially in the peripheral nervous system (PNS) and heart. PNS involvement leads to a rapidly progressive and disabling sensory‐motor axonal neuropathy. Although awareness among neurologists increased in recent years thanks to new treatment options, ATTRv is frequently misdiagnosed, and thus a correct diagnosis can be delayed by several years. This review aims to draw the history and features of polyneuropathy in ATTRv based on pathological and electrophysiological correlates. We assessed original articles and case reports based on their relevance to ATTRv neuropathy and we included those appropriate for the scheme of this narrative review. Amyloid fibrils initially deposit in ganglia, causing an axonal neuropathy without amyloid deposits in distal segments (eg, sural nerve biopsy). Over time, amyloid fibrils spread along the nerves, leading to some demyelinating features in the context of severe axonal loss. This review highlights how the features of neuropathy change based on type of ATTRv (early vs late onset) and stage of disease.
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Affiliation(s)
- Stefano Tozza
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Daniele Severi
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Emanuele Spina
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Aniello Iovino
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Francesco Aruta
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Lucia Ruggiero
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Raffaele Dubbioso
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Rosa Iodice
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Maria Nolano
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
| | - Fiore Manganelli
- Department of Neuroscience, Reproductive and Odontostomatological Science, University of Naples "Federico II", Naples, Italy
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9
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Wang TKM, Abou Hassan OK, Jaber W, Xu B. Multi-modality imaging of cardiac amyloidosis: Contemporary update. World J Radiol 2020; 12:87-100. [PMID: 32742575 PMCID: PMC7364284 DOI: 10.4329/wjr.v12.i6.87] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/13/2020] [Accepted: 06/02/2020] [Indexed: 02/06/2023] Open
Abstract
Cardiac amyloidosis is a heterogeneous and challenging diagnostic disease with poor prognosis that is now being altered by introduction of new therapies. Echocardiography remains the first-line imaging tool, and when disease is suspected on echocardiography, cardiac magnetic resonance imaging and nuclear imaging play critical roles in the non-invasive diagnosis and evaluation of cardiac amyloidosis. Advances in multi-modality cardiac imaging allowing earlier diagnosis and initiation of novel therapies have significantly improved the outcomes in these patients. Cardiac imaging also plays important roles in the risk stratification of patients presenting with cardiac amyloidosis. In the current review, we provide a clinical and imaging focused update, and importantly outline the imaging protocols, diagnostic and prognostic utility of multimodality cardiac imaging in the assessment of cardiac amyloidosis.
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Affiliation(s)
- Tom Kai Ming Wang
- Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Ossama K Abou Hassan
- Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Wael Jaber
- Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Bo Xu
- Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, United States
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10
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Low Sensitivity of Bone Scintigraphy in Detecting Phe64Leu Mutation-Related Transthyretin Cardiac Amyloidosis. JACC Cardiovasc Imaging 2020; 13:1314-1321. [DOI: 10.1016/j.jcmg.2019.10.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 10/07/2019] [Accepted: 10/11/2019] [Indexed: 11/29/2022]
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11
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Conceição I. Response: Suhr OB: commentary to Isabel Conceição et al. early diagnosis through targeted follow-up of identified carriers of TTR gene mutations. Amyloid 2019; 26:248-249. [PMID: 31364873 DOI: 10.1080/13506129.2019.1642191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Isabel Conceição
- Department of Neurology, CHULN-HSM and Fac Med-IMM, Universidade de Lisboa , Lisboa , Portugal
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12
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Suhr OB. Response: concerning "late early and late onset" ATTR Val30Met patients. Amyloid 2019; 26:250. [PMID: 31554437 DOI: 10.1080/13506129.2019.1642192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Ole B Suhr
- Department of Public Health and Clinical Medicine, Umeå University , Umeå , Sweden
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13
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Park GY, Jamerlan A, Shim KH, An SSA. Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases. Int J Mol Sci 2019; 20:E2982. [PMID: 31216785 PMCID: PMC6628571 DOI: 10.3390/ijms20122982] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 06/10/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023] Open
Abstract
Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.
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Affiliation(s)
- Gil Yong Park
- Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si 13120, Korea.
| | - Angelo Jamerlan
- Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si 13120, Korea.
| | - Kyu Hwan Shim
- Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si 13120, Korea.
| | - Seong Soo A An
- Department of Bionano Technology, Gachon Medical Research Institute, Gachon University, Seongnam-si 13120, Korea.
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14
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Ueda M, Okada M, Mizuguchi M, Kluve-Beckerman B, Kanenawa K, Isoguchi A, Misumi Y, Tasaki M, Ueda A, Kanai A, Sasaki R, Masuda T, Inoue Y, Nomura T, Shinriki S, Shuto T, Kai H, Yamashita T, Matsui H, Benson MD, Ando Y. A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH. J Biol Chem 2019; 294:11259-11275. [PMID: 31167790 DOI: 10.1074/jbc.ra119.007851] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/31/2019] [Indexed: 12/12/2022] Open
Abstract
Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81-127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81-127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81-127-based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis.
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Affiliation(s)
- Mitsuharu Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Masamitsu Okada
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Mineyuki Mizuguchi
- Laboratory of Structural Biology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
| | - Barbara Kluve-Beckerman
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Kyosuke Kanenawa
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Aito Isoguchi
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Yohei Misumi
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Masayoshi Tasaki
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan.,Department of Morphological and Physiological Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto 862-0976, Japan
| | - Akihiko Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Akinori Kanai
- Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Ryoko Sasaki
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Teruaki Masuda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Yasuteru Inoue
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Toshiya Nomura
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Satoru Shinriki
- Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Tsuyoshi Shuto
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Hirofumi Kai
- Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
| | - Taro Yamashita
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Hirotaka Matsui
- Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Merrill D Benson
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Yukio Ando
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
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