Lisa Mendelson, Tatiana Prokaeva, K H Vincent Lau, Vaishali Sanchorawala, Kristen McCausland, Brian Spencer, Surendra Dasari, Ellen D McPhail, Michelle C Kaku
{"title":"Hereditary gelsolin amyloidosis: a rare cause of cranial, peripheral and autonomic neuropathies linked to D187N and Y447H substitutions.","authors":"Lisa Mendelson, Tatiana Prokaeva, K H Vincent Lau, Vaishali Sanchorawala, Kristen McCausland, Brian Spencer, Surendra Dasari, Ellen D McPhail, Michelle C Kaku","doi":"10.1080/13506129.2023.2204999","DOIUrl":"10.1080/13506129.2023.2204999","url":null,"abstract":"<p><strong>Introduction: </strong>Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States.</p><p><strong>Methods: </strong>Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews.</p><p><strong>Results: </strong>Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis.</p><p><strong>Discussion: </strong>We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9397959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tim Moderer, Ioana Puşcalău-Gîrţu, Christian Haupt, Julian Baur, Armando Rodríguez-Alfonso, Sebastian Wiese, Christoph Q Schmidt, Miroslav Malešević, Wolf-Georg Forssmann, Ludger Ständker, Marcus Fändrich
{"title":"Human lysozyme inhibits the fibrillation of serum amyloid a protein from systemic AA amyloidosis.","authors":"Tim Moderer, Ioana Puşcalău-Gîrţu, Christian Haupt, Julian Baur, Armando Rodríguez-Alfonso, Sebastian Wiese, Christoph Q Schmidt, Miroslav Malešević, Wolf-Georg Forssmann, Ludger Ständker, Marcus Fändrich","doi":"10.1080/13506129.2023.2232518","DOIUrl":"10.1080/13506129.2023.2232518","url":null,"abstract":"<p><strong>Background: </strong>Systemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs.</p><p><strong>Objective: </strong>To identify new agents that prevent fibril formation from SAA protein and to determine their mode of action.</p><p><strong>Materials and methods: </strong>We used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods.</p><p><strong>Results: </strong>We identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids.</p><p><strong>Conclusion: </strong>Our data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9769793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Iatrogenic cerebral amyloid angiopathy rather than sporadic CAA in younger adults with lobar intracerebral haemorrhage.","authors":"J C Purrucker, C Röcken, D Reuss","doi":"10.1080/13506129.2023.2212394","DOIUrl":"10.1080/13506129.2023.2212394","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9816463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Treitz, Neelis Müller-Marienburg, Rolf Rüdiger Meliß, Peter Urban, Hans-Detlef Axmann, Frank Siebert, Karsten Becker, Klaus Martens, Hans-Michael Behrens, Eva Gericke, Andreas Tholey, Christoph Röcken
{"title":"ATTR- and AFib amyloid - two different types of amyloid in the annular ligament of trigger finger.","authors":"Christian Treitz, Neelis Müller-Marienburg, Rolf Rüdiger Meliß, Peter Urban, Hans-Detlef Axmann, Frank Siebert, Karsten Becker, Klaus Martens, Hans-Michael Behrens, Eva Gericke, Andreas Tholey, Christoph Röcken","doi":"10.1080/13506129.2023.2226298","DOIUrl":"10.1080/13506129.2023.2226298","url":null,"abstract":"<p><strong>Introduction: </strong>Histological examination of tissue specimens obtained during surgical treatment of trigger finger frequently encountered unclassifiable amyloid deposits in the annular ligament. We systematically explored this unknown type by a comprehensive analysis using histology, immunohistochemistry, and quantitative mass spectrometry-based proteomics.</p><p><strong>Methods: </strong>205 tissue specimens of annular ligaments were obtained from 172 patients. Each specimen was studied by histology and immunohistochemistry. Tissue specimens obtained from ten patients with histology proven amyloid in annular ligament were analysed by label-free quantitative proteomics. Histological and immunohistochemical findings were correlated with patient demographics.</p><p><strong>Results: </strong>Amyloid was present as band like deposits along the surface of annular ligament, dot like or patchy deposits within the matrix. Immunohistochemistry identified ATTR amyloid in 92 specimens (mostly patchy in the matrix), while the band like deposits of 100 specimens remained unclassifiable. Proteomic profiles identified the unknown amyloid as most likely of fibrinogen origin. The complete cohort was re-examined by immunohistochemistry using a custom-made antibody and confirmed the presence of fibrinogen alpha-chain (FGA) in a hitherto unclassifiable type of amyloid in annular ligament.</p><p><strong>Conclusion: </strong>Our study shows that two different types of amyloid affect the annular ligament, ATTR amyloid and AFib amyloid, with distinct demographic patient characteristics and histomorphological deposition patterns.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9678601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Marchi, Chiara Kessler, Daniela Distefano, Lodovico Terzi di Bergamo, Luca Fumagalli, Manuela Averaimo, Emanuele Crupi, Fabio Bergamini, Giorgia Melli, Georg Stussi, Davide Rossi, Claudio Gobbi, Paolo Ripellino, Emanuele Pravatà, Dominique E Kuhlen, Christoph Röcken, Pietro Scarone, Bernhard Gerber, Adalgisa Condoluci
{"title":"Prevalence of amyloid in ligamentum flavum of patients with lumbar spinal stenosis.","authors":"Francesco Marchi, Chiara Kessler, Daniela Distefano, Lodovico Terzi di Bergamo, Luca Fumagalli, Manuela Averaimo, Emanuele Crupi, Fabio Bergamini, Giorgia Melli, Georg Stussi, Davide Rossi, Claudio Gobbi, Paolo Ripellino, Emanuele Pravatà, Dominique E Kuhlen, Christoph Röcken, Pietro Scarone, Bernhard Gerber, Adalgisa Condoluci","doi":"10.1080/13506129.2023.2230516","DOIUrl":"10.1080/13506129.2023.2230516","url":null,"abstract":"<p><strong>Background: </strong>Transthyretin (ATTR) amyloidosis is often diagnosed in an advanced stage, when irreversible cardiac damage has occurred. Lumbar spinal stenosis (LSS) may precede cardiac ATTR amyloidosis by many years, offering the opportunity to detect ATTR already at the time of LSS surgery. We prospectively assessed the prevalence of ATTR in the ligamentum flavum by tissue biopsy in patients aged >50 years undergoing surgery for LSS.</p><p><strong>Methods: </strong>Ligamentum flavum thickness was assessed pre-operatively on axial T2 magnetic resonance imaging (MRI) slices. Tissue samples from ligamentum flavum were screened centrally by Congo red staining and immunohistochemistry (IHC).</p><p><strong>Results: </strong>Amyloid in the ligamentum flavum was detected in 74/94 patients (78.7%). IHC revealed ATTR in 61 (64.9%), whereas amyloid subtyping was inconclusive in 13 (13.8%). Mean thickness of ligamentum flavum was significantly higher at all levels in patients with amyloid (<i>p</i> < .05). Patients with amyloid deposits were older (73.1 ± 9.2 vs. 64.6 ± 10.1 years, <i>p</i> = .01). No differences in sex, comorbidities, previous surgery for carpal tunnel syndrome or LSS were observed.</p><p><strong>Conclusions: </strong>Amyloid, mostly of the ATTR subtype, was found in four out of five patients with LSS and is associated with age and ligamentum flavum thickness. Histopathological work-up of ligamentum flavum might inform future decision making.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9769792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bengt Zöller, Eric Manderstedt, Christina Lind-Halldén, Christer Halldén
{"title":"Rare-variant collapsing and bioinformatic analyses for amyloidosis, dementia and Parkinson's disease in the UK biobank reveal novel susceptibility loci.","authors":"Bengt Zöller, Eric Manderstedt, Christina Lind-Halldén, Christer Halldén","doi":"10.1080/13506129.2023.2226299","DOIUrl":"10.1080/13506129.2023.2226299","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9781141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Teresa Coelho, Angela Dispenzieri, Martha Grogan, Isabel Conceição, Márcia Waddington-Cruz, Arnt V Kristen, Jonas Wixner, Igor Diemberger, Juan Gonzalez-Moreno, Mathew S Maurer, Violaine Planté-Bordeneuve, Pablo Garcia-Pavia, Ivailo Tournev, Jose Gonzalez-Costello, Eve Cariou, Alejandra González-Duarte, Oliver Glass, Doug Chapman, Leslie Amass
{"title":"Patients with transthyretin amyloidosis enrolled in THAOS between 2018 and 2021 continue to experience substantial diagnostic delay.","authors":"Teresa Coelho, Angela Dispenzieri, Martha Grogan, Isabel Conceição, Márcia Waddington-Cruz, Arnt V Kristen, Jonas Wixner, Igor Diemberger, Juan Gonzalez-Moreno, Mathew S Maurer, Violaine Planté-Bordeneuve, Pablo Garcia-Pavia, Ivailo Tournev, Jose Gonzalez-Costello, Eve Cariou, Alejandra González-Duarte, Oliver Glass, Doug Chapman, Leslie Amass","doi":"10.1080/13506129.2023.2229484","DOIUrl":"10.1080/13506129.2023.2229484","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9882057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bharadwaj Satyavolu, Genise Green, Anthony Jake Demetris, Prem Soman
{"title":"A rare occurrence and near miss! Should a TTR gene test be routinely performed for suspected ATTR-cardiomyopathy?","authors":"Bharadwaj Satyavolu, Genise Green, Anthony Jake Demetris, Prem Soman","doi":"10.1080/13506129.2023.2232516","DOIUrl":"10.1080/13506129.2023.2232516","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9757535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sabrina Ghosh, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Devin Kenney, Carly S Golden, Camille V Edwards, Vaishali Sanchorawala, Lawreen H Connors, Richard M Giadone, George J Murphy
{"title":"Mapping cellular response to destabilized transthyretin reveals cell- and amyloidogenic protein-specific signatures.","authors":"Sabrina Ghosh, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Devin Kenney, Carly S Golden, Camille V Edwards, Vaishali Sanchorawala, Lawreen H Connors, Richard M Giadone, George J Murphy","doi":"10.1080/13506129.2023.2224494","DOIUrl":"10.1080/13506129.2023.2224494","url":null,"abstract":"<p><strong>Background: </strong>In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive.</p><p><strong>Methods: </strong>In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTR<sup>V122I</sup> (p.V142I) and TTR<sup>L55P</sup> (p.L70P)) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock).</p><p><strong>Results: </strong>In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR that resolved upon pre-incubation with kinetic stabilizer tafamidis.</p><p><strong>Conclusions: </strong>Collectively, these data provide insight into the mechanisms underlying destabilized protein-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9985612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Elena S Klimtchuk, Daniele Peterle, Esther Bullitt, Lawreen H Connors, John R Engen, Olga Gursky
{"title":"Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains.","authors":"Elena S Klimtchuk, Daniele Peterle, Esther Bullitt, Lawreen H Connors, John R Engen, Olga Gursky","doi":"10.1080/13506129.2023.2212397","DOIUrl":"10.1080/13506129.2023.2212397","url":null,"abstract":"<p><strong>Background: </strong>Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease complicated by vast numbers of patient-specific mutations. We explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01.</p><p><strong>Methods: </strong>Hydrogen-deuterium exchange mass spectrometry analysis of conformational dynamics in recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation and amyloidogenic sequence propensity. The results were mapped on the structures of native and fibrillary proteins.</p><p><strong>Results: </strong>Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower, suggesting different major factors influencing amyloidogenesis. In 33*01-related amyloid LC, these factors involved destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC stemmed from increased dynamics/exposure of amyloidogenic segments in βC'V and βEV that could initiate aggregation and decreased dynamics/exposure near the Cys23-Cys88 disulfide.</p><p><strong>Conclusions: </strong>The results suggest distinct amyloidogenic pathways for closely related LCs and point to the complementarity-defining regions CDR1 and CDR3, linked via the conserved internal disulfide, as key factors in amyloid formation.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10663386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9552302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}