Amyloid-Journal of Protein Folding Disorders最新文献

{"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":" ","pages":"442-444"},"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}

{"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":" ","pages":"449-450"},"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}

{"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":" ","pages":"445-448"},"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}

{"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^V122I (p.V142I) and TTR^L55P (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":" ","pages":"379-393"},"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}

{"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":" ","pages":"364-378"},"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}

{"title":"Neuropathy progression in hereditary transthyretin amyloidosis (ATTRv) patients after liver transplantation.","authors":"Catarina Falcão de Campos, Isabel Conceição","doi":"10.1080/13506129.2023.2226295","DOIUrl":"10.1080/13506129.2023.2226295","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":" ","pages":"440-441"},"PeriodicalIF":5.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9670809","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":"Tafamidis concentration required for transthyretin stabilisation in cerebrospinal fluid.","authors":"Felix J Tsai, Marcus Jaeger, Teresa Coelho, Evan T Powers, Jeffery W Kelly","doi":"10.1080/13506129.2023.2167595","DOIUrl":"10.1080/13506129.2023.2167595","url":null,"abstract":"<p><strong>Background: </strong>Hereditary transthyretin (TTR) amyloidosis (ATTRv) initially presents as a polyneuropathy and/or a cardiomyopathy. Central nervous system (CNS) pathology in ATTRv amyloidosis, including focal neurological episodes, dementia, cerebrovascular bleeding, and seizures, appears around a decade later. Wild-type (WT) TTR amyloidosis (ATTRwt) causes a cardiomyopathy. CNS pathology risk likely also increases in these patients as cardiomyopathy progresses. Herein, we study tafamidis-mediated TTR kinetic stabilisation in cerebrospinal fluid (CSF).</p><p><strong>Methods: </strong>Varying tafamidis concentrations (50-1000 nM) were added to CSF from healthy donors or ATTRv patients, and TTR stabilisation was measured <i>via</i> the decrease in dissociation rate.</p><p><strong>Results: </strong>Tafamidis meglumine (Vyndaqel) can be dosed at 20 or 80 mg QD. The latter dose is bioequivalent to a 61 mg QD dose of tafamidis free acid (Vyndamax). The tafamidis CSF concentration in ATTRv patients on 20 mg Vyndaqel is ∼125 nM. By linear extrapolation, we expect a CSF concentration of ∼500 nM at the higher dose. When tafamidis is added to healthy donor CSF at 125 or 500 nM, the WT TTR dissociation rate decreases by 42% or 87%, respectively.</p><p><strong>Conclusions: </strong>Tafamidis stabilises TTR in CSF to what is likely a clinically meaningful extent at CSF concentrations achieved by the normal tafamidis dosing regimen.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":"30 3","pages":"279-289"},"PeriodicalIF":5.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10363573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10056975","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}

{"title":"Neurofilament light chain as a biomarker for monitoring response to change in treatment in hereditary ATTR amyloidosis.","authors":"Mitsuto Sato,&nbsp;Yusuke Mochizuki,&nbsp;Yusuke Takahashi,&nbsp;Ken Takasone,&nbsp;Emre Aldinc,&nbsp;Simina Ticau,&nbsp;Gang Jia,&nbsp;Yoshiki Sekijima","doi":"10.1080/13506129.2023.2187678","DOIUrl":"https://doi.org/10.1080/13506129.2023.2187678","url":null,"abstract":"Hereditary ATTR (ATTRv) amyloidosis is a fatal autosomal dominant disorder in which variants in the transthyretin (TTR) gene cause systemic deposition of amyloid fibrils. ATTRv amyloidosis is characterised by progressive lengthdependent sensorimotor neuropathy, autonomic neuropathy, and non-neuropathic manifestations [1]. Several effective pharmacological therapies are available, including TTR tetramer stabilisers (diflunisal and tafamidis) and nucleic acid-based medications such as RNA interference therapeutics (patisiran and vutrisiran) and anti-sense oligonucleotide (inotersen) [1,2]. However, evaluation and monitoring of disease progression and treatment response are challenging in clinical practice, because existing assessment methods are not sensitive enough to detect changes in disease activity. Neurofilament light chain (NfL) is an integral component of the neurons, and has been described as a biomarker of neuroaxonal injury across several central and peripheral nervous system diseases. Additionally, recent analyses have identified NfL as a potential biomarker of neuronal injury in ATTRv amyloidosis [3,4]. In this analysis, we evaluated the value of NfL in monitoring treatment response in patients with ATTRv amyloidosis with polyneuropathy whose treatment was switched from tafamidis to patisiran. Eleven patients (10 male) with ATTRv amyloidosis with polyneuropathy who switched treatment from tafamidis (20mg oral once daily) to patisiran (0.3mg/kg IV once in every three weeks) were included. The reason for switch was worsening of polyneuropathy. Serum NfL levels of patients were measured at baseline (while receiving tafamidis, just before switch), one and two years after switch to patisiran. In eight of the eleven patients, NfL levels were available at two years following switch. Patients were also assessed for neurologic impairment with neuropathy impairment score (NIS) at baseline and one and/or two years following switch. Since the patients were assessed during routine visits, NfL and NIS measurements at 1-year and 2-year post-switch occurred within 3months of those time points, except one patient whose 2-year measurements were delayed by four months. NfL levels were measured using the QuanterixR Simoa platform. The Wilcoxon signed-rank test was used to compare NfL levels and NIS values before, and one and two years after switch to patisiran. p&lt; 0.05 was considered statistically significant. This study was approved by the Ethical Committee of Shinshu University School of Medicine (No. 4852) and written informed consent was obtained from patients. Mean (±SD) age at disease onset and study inclusion were 39.5 ± 12.6 and 46.9 ± 14.0 years, respectively. TTR variants were V30M (p.V50M) (n1⁄4 8), A36P (p.A56P), S50A (p.S70A), and I107V (p.I127V), (n1⁄4 1 each). NfL and NIS measurements at baseline were available for all 11 patients. Serum NfL levels were available for 11/11 and 8/11 patients at one and two years following switch, respectivel","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":"30 3","pages":"351-352"},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10060175","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":"Impact of cytogenetic abnormalities on treatment outcomes in patients with amyloid light-chain amyloidosis: subanalyses from the ANDROMEDA study.","authors":"Shaji Kumar,&nbsp;Angela Dispenzieri,&nbsp;Divaya Bhutani,&nbsp;Morie Gertz,&nbsp;Ashutosh Wechalekar,&nbsp;Giovanni Palladini,&nbsp;Raymond Comenzo,&nbsp;Rafael Fonseca,&nbsp;Arnaud Jaccard,&nbsp;Efstathios Kastritis,&nbsp;Stefan Schönland,&nbsp;Charles la Porte,&nbsp;Huiling Pei,&nbsp;NamPhuong Tran,&nbsp;Giampaolo Merlini","doi":"10.1080/13506129.2022.2164488","DOIUrl":"https://doi.org/10.1080/13506129.2022.2164488","url":null,"abstract":"<p><strong>Background: </strong>Cytogenetic abnormalities are common in patients with amyloid light-chain (AL) amyloidosis; some are associated with poorer outcomes. This post hoc analysis of ANDROMEDA evaluated the impact of certain cytogenetic abnormalities on outcomes in this patient population.</p><p><strong>Methods: </strong>Patients with newly diagnosed AL amyloidosis were randomised 1:1 to daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) or VCd. Outcomes were evaluated in the intent-to-treat (ITT) population and in patients with t(11;14), amp1q21, del13q14, and del17p13.</p><p><strong>Results: </strong>Overall, 321 patients had cytogenetic testing (D-VCd, <i>n</i> = 155; VCd, <i>n</i> = 166); most common abnormalities were t(11;14) and amp1q21. At a median follow-up of 20.3 months, haematologic complete response rates were higher with D-VCd vs VCd across all cytogenetic subgroups and organ response rates were numerically higher with D-VCd vs VCd across most subgroups. Point estimates for hazard ratio of major organ deterioration-PFS and -EFS favoured D-VCd over VCd for all cytogenetic subgroups. Deep haematologic responses (involved minus uninvolved free light chains [FLC] <10 mg/L or involved FLC ≤20 mg/L) were seen in more patients with D-VCd than VCd in all ITT and t(11;14) cohorts.</p><p><strong>Conclusions: </strong>These results support the use of D-VCd as standard of care in patients with newly diagnosed AL amyloidosis regardless of cytogenetic abnormalities.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":"30 3","pages":"268-278"},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10100063","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":"Collagen inhibits phagocytosis of amyloid <i>in vitro</i> and <i>in vivo</i> and may act as a 'don't eat me' signal.","authors":"Joseph W Jackson,&nbsp;James S Foster,&nbsp;Emily B Martin,&nbsp;Sallie Macy,&nbsp;Craig Wooliver,&nbsp;Manasi Balachandran,&nbsp;Tina Richey,&nbsp;R Eric Heidel,&nbsp;Angela D Williams,&nbsp;Stephen J Kennel,&nbsp;Jonathan S Wall","doi":"10.1080/13506129.2022.2155133","DOIUrl":"https://doi.org/10.1080/13506129.2022.2155133","url":null,"abstract":"<p><strong>Background: </strong>Systemic amyloidosis refers to a group of protein misfolding disorders characterized by the extracellular deposition of amyloid fibrils in organs and tissues. For reasons heretofore unknown, amyloid deposits are not recognized by the immune system, and progressive deposition leads to organ dysfunction.</p><p><strong>Methods: </strong><i>In vitro</i> and <i>in vivo</i> phagocytosis assays were performed to elucidate the impact of collagen and other amyloid associated proteins (eg serum amyloid p component and apolipoprotein E) had on amyloid phagocytosis. Immunohistochemical and histopathological staining regimens were employed to analyze collagen-amyloid interactions and immune responses.</p><p><strong>Results: </strong>Histological analysis of amyloid-laden tissue indicated that collagen is intimately associated with amyloid deposits. We report that collagen inhibits phagocytosis of amyloid fibrils by macrophages. Treatment of 15 patient-derived amyloid extracts with collagenase significantly enhanced amyloid phagocytosis. Preclinical mouse studies indicated that collagenase treatment of amyloid extracts significantly enhanced clearance as compared to controls, coincident with increased immune cell infiltration of the subcutaneous amyloid lesion.</p><p><strong>Conclusions: </strong>These data suggest that amyloid-associated collagen serves as a 'don't eat me' signal, thereby hindering clearance of amyloid. Targeted degradation of amyloid-associated collagen could result in innate immune cell recognition and clearance of pathologic amyloid deposits.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":"30 3","pages":"249-260"},"PeriodicalIF":5.5,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10040405","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}