Amyloid-Journal of Protein Folding Disorders最新文献

{"title":"Predictors of cognitive dysfunction in hereditary transthyretin amyloidosis with liver transplant.","authors":"Sara Cavaco,&nbsp;Ana Martins da Silva,&nbsp;Joana Fernandes,&nbsp;Ana Paula Sousa,&nbsp;Cristina Alves,&nbsp;Márcio Cardoso,&nbsp;Armando Teixeira-Pinto,&nbsp;Teresa Coelho","doi":"10.1080/13506129.2022.2131384","DOIUrl":"https://doi.org/10.1080/13506129.2022.2131384","url":null,"abstract":"<p><strong>Background: </strong>Cognitive dysfunction is part of the broad spectrum of clinical manifestations in older untreated hereditary transthyretin amyloidosis patients with peripheral polyneuropathy.</p><p><strong>Objective: </strong>The objective of this study is to systematically explore cognitive dysfunction in ATTRV30M amyloidosis patients whose disease course was modified by liver transplant (LT).</p><p><strong>Methods: </strong>A series of 269 carriers of TTRVal30Met mutation treated with LT underwent a neuropsychological assessment. Clinical charts were reviewed to identify focal neurological episodes (FNEs), cognitive complaints and laboratory results. Chi-square and Mann-Whitney tests explored potential predictors of cognitive dysfunction.</p><p><strong>Results: </strong>Cognitive dysfunction was identified in 35 patients (13%)-14 (5%) had mild and 21 (8%) had moderate dysfunction. In comparison to normal cognition, both mild and moderate cognitive dysfunction patients had older age, higher mPND score and elevated NT-proBNP and Cystatin C values. Mild cognitive dysfunction was associated with longer disease duration and history of FNEs, whereas moderate dysfunction was related to older age at disease onset and more cognitive complaints and depression symptoms.</p><p><strong>Conclusions: </strong>Consistent with the natural history of the disease, older age and higher severity of the disease are significantly associated and potentially predictors of cognitive dysfunction in ATTRV30M patients treated with LT. The level of cognitive dysfunction may depend on some clinical variables.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10818704","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 tafamidis on myocardial strain in transthyretin amyloid cardiomyopathy.","authors":"René Rettl,&nbsp;Franz Duca,&nbsp;Christina Binder,&nbsp;Theresa-Marie Dachs,&nbsp;Bernhard Cherouny,&nbsp;Luciana Camuz Ligios,&nbsp;Christopher Mann,&nbsp;Lore Schrutka,&nbsp;Daniel Dalos,&nbsp;Silvia Charwat-Resl,&nbsp;Roza Badr Eslam,&nbsp;Johannes Kastner,&nbsp;Diana Bonderman","doi":"10.1080/13506129.2022.2131385","DOIUrl":"https://doi.org/10.1080/13506129.2022.2131385","url":null,"abstract":"<p><strong>Aims: </strong>The impact of tafamidis on myocardial strain in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) have been barely investigated. We aimed to determine tafamidis-induced changes using serial speckle tracking echocardiography and to identify imaging parameters for specific therapy monitoring.</p><p><strong>Methods and results: </strong>ATTR-CM patients underwent serial TTE with two-dimensional (2 D) speckle tracking imaging. Patients receiving tafamidis free acid 61 mg (<i>n</i> = 62) or tafamidis meglumine 20 mg (<i>n</i> = 21) once daily (QD) showed stable measurements at follow-up (61 mg: 8.5 months, 20 mg: 7.0 months) in LV global longitudinal strain (GLS) (61 mg: -11.75% vs. -11.58%, <i>p</i> = 0.534; 20 mg: -10.61% vs. -10.12%, <i>p</i> = 0.309), right ventricular (RV) GLS (61 mg: -14.18% vs. -13.72%, <i>p</i> = 0.377; 20 mg: -14.53% vs. -13.99%, <i>p</i> = 0.452) and left atrial (LA) reservoir strain (LASr; 61 mg: 8.80% vs. 9.42%, <i>p</i> = 0.283; 20 mg: 8.23% vs. 8.67%, <i>p</i> = 0.589), whereas treatment-naïve ATTR-CM patients (<i>n</i> = 54) had clear signs of disease progression at the end of the observation period (10.5 months; LV-GLS: -11.71% vs. -10.59%, <i>p</i> = 0.001; RV-GLS: -14.36% vs. -12.99%, <i>p</i> = 0.038; LASr: 10.67% vs. 8.41%, <i>p</i> = 0.005). Between-group comparison at follow-up revealed beneficial effects of tafamidis free acid 61 mg on LASr (<i>p</i> = 0.003) and the LV (LV-GLS: <i>p</i> = 0.030, interventricular septum (IVS): <i>p</i> = 0.006), resulting in clinical benefits (six-minute walk distance (6-MWD): <i>p</i> = 0.006, NT-proBNP: p= <0.001), while patients treated with tafamidis meglumine 20 mg QD showed positive effects on LASr (<i>p</i> = 0.039), but no differences with respect to the LV (LV-GLS: <i>p</i> = 0.274, IVS: <i>p</i> = 0.068) and clinical status (6-MWD: <i>p</i> = 0.124, NT-proBNP: <i>p</i> = 0.053) compared to the natural course.</p><p><strong>Conclusions: </strong>Treatment with tafamidis free acid 61 mg in ATTR-CM patients delays the deterioration of LA and LV longitudinal function, resulting in significant clinical benefits compared with natural history. Serial TTE with 2 D speckle tracking imaging may be appropriate for disease-specific therapy monitoring.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10818702","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":"Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group.","authors":"Ashutosh D Wechalekar,&nbsp;M Teresa Cibeira,&nbsp;Simon D Gibbs,&nbsp;Arnaud Jaccard,&nbsp;Shaji Kumar,&nbsp;Giampaolo Merlini,&nbsp;Giovanni Palladini,&nbsp;Vaishali Sanchorawala,&nbsp;Stefan Schönland,&nbsp;Christopher Venner,&nbsp;Mario Boccadoro,&nbsp;Efstathios Kastritis","doi":"10.1080/13506129.2022.2093635","DOIUrl":"https://doi.org/10.1080/13506129.2022.2093635","url":null,"abstract":"<p><strong>Background: </strong>This guideline has been developed jointly by the European Society of Haematology and International Society of Amyloidosis recommending non-transplant chemotherapy treatment for patients with AL amyloidosis.</p><p><strong>Methods: </strong>A review of literature and grading of evidence as well as expert recommendations by the ESH and ISA guideline committees.</p><p><strong>Results and conclusions: </strong>The recommendations of this committee suggest that treatment follows the clinical presentation which determines treatment tolerance tempered by potential side effects to select and modify use of drugs in AL amyloidosis. All patients with AL amyloidosis should be considered for clinical trials where available. Daratumumab-VCD is recommended from most untreated patients (VCD or VMDex if daratumumab is unavailable). At relapse, the two guiding principles are the depth and duration of initial response, use of a class of agents not previously exposed as well as the limitation imposed by patients' fitness/frailty and end organ damage. Targeted agents like venetoclax need urgent prospective evaluation. Future prospective trials should include advanced stage patients to allow for evidence-based treatment decisions. Therapies targeting amyloid fibrils or those reducing the proteotoxicity of amyloidogenic light chains/oligomers are urgently needed.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9117259","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":"Binding of serum-derived amyloid-associated proteins to amyloid fibrils.","authors":"Yohei Misumi,&nbsp;Yuri Tabata,&nbsp;Masayoshi Tasaki,&nbsp;Konen Obayashi,&nbsp;Shiori Yamakawa,&nbsp;Toshiya Nomura,&nbsp;Mitsuharu Ueda","doi":"10.1080/13506129.2022.2120800","DOIUrl":"https://doi.org/10.1080/13506129.2022.2120800","url":null,"abstract":"<p><strong>Background: </strong>Amyloid signature proteins such as serum amyloid P component, apolipoprotein E (ApoE), and ApoA-IV generally co-localise with amyloid, regardless of the types of amyloid precursor protein or the organs. Most of these proteins derive from serum and have reportedly been involved in amyloid fibril formation and stabilisation, as well as in excretion and degradation of amyloid precursor proteins. However, the processes and mechanisms by which these specific proteins deposit together with amyloid fibrils have not been clarified.</p><p><strong>Methods: </strong>We analysed the binding of serum proteins to amyloid fibrils derived from amyloid <i>β</i> and insulin <i>in vitro</i> by using liquid chromatography-tandem mass spectrometry (LC-MS/MS).</p><p><strong>Results: </strong>Specific serum proteins including ApoA-I, ApoE, ApoA-IV, ApoC-III and vitronectin adhered to amyloid fibrils at high concentrations <i>in vitro</i>. In addition, the profile of these proteins commonly occurred in both amyloid β and insulin amyloid fibrils and was mostly consistent with the composition of amyloid signature proteins. We also showed that high concentrations of serum proteins can adhere to amyloid fibrils in a short time.</p><p><strong>Conclusions: </strong>Our <i>in vitro</i> results suggest that amyloid signature proteins coexist with amyloid primarily dependent on the binding of each serum protein, in the extracellular fluid, to amyloid fibrils.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9390793","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":"Distribution and progression of cerebral amyloid angiopathy in early-onset V30M (p.V50M) hereditary ATTR amyloidosis.","authors":"Yusuke Takahashi,&nbsp;Kazuhiro Oguchi,&nbsp;Yusuke Mochizuki,&nbsp;Ken Takasone,&nbsp;Naoki Ezawa,&nbsp;Akira Matsushima,&nbsp;Nagaaki Katoh,&nbsp;Masahide Yazaki,&nbsp;Yoshiki Sekijima","doi":"10.1080/13506129.2022.2128331","DOIUrl":"https://doi.org/10.1080/13506129.2022.2128331","url":null,"abstract":"<p><strong>Background: </strong>Cerebral amyloid angiopathy (CAA) is becoming the most common and serious complications in long-lived hereditary ATTR amyloidosis patients. It is therefore imperative to elucidate the characteristics of ATTR-type CAA and develop useful biomarkers.</p><p><strong>Methods: </strong>We enrolled 34 ATTRv amyloidosis patients with the V30M (p.V50M) variant for analysis with three-dimensional stereotactic surface projection <i>z</i> score imaging of Pittsburgh compound B (PiB)-PET.</p><p><strong>Results: </strong>Eight patients exhibited central nervous system (CNS) symptoms. Seven patients suffered transient focal neurologic episodes, and 2 patients each experienced cerebellar haemorrhages or cognitive decline. The amount of ¹¹C-PiB accumulation increased as a function of disease duration. ¹¹C-PiB-PET abnormalities were seen at 8 years from onset and were associated with CNS manifestations from 12 years. The annual increase rate of the standardised uptake value ratio (SUVR) in female patients was significantly higher than in male patients. CNS amyloid deposition started in the upper middle surface of the cerebellar cortex, and then spread out over the entire surface of the cerebellum, Sylvian fissure, and anterior part of the longitudinal fissure of the cerebrum.</p><p><strong>Conclusions: </strong>PiB-PET is a useful biomarker for the early detection and treatment evaluation of ATTR-type CAA. Female gender is associated with more rapid progression of ATTR-type CAA.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9391263","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":"Selective recognition of human small transthyretin aggregates by a novel monoclonal antibody.","authors":"A C Teixeira,&nbsp;Maria J Saraiva","doi":"10.1080/13506129.2022.2122034","DOIUrl":"https://doi.org/10.1080/13506129.2022.2122034","url":null,"abstract":"<p><p>Biochemical characterisation of transthyretin variant TTR Y78F showed that this variant adopts a tetrameric conformation as normal TTR but exhibits some of the characteristics of an intermediate structure in the fibrillogenesis pathway. It was hypothesised that native Y78F might represent an early event in TTR amyloidogenesis. We immunised TTR knock out mice with recombinant variant TTR Y78F. One stable hybridoma named CE11, of the IgM isotype, was tested for reactivity towards several soluble recombinant TTR variants both amyloidogenic and non-amyloidogenic. CE11 only recognises the highly amyloidogenic TTR variants L55P, S52P, A97S, Y78F or acidified TTR wt preparations. At the same time, this clone was negative for TTR V30M, soluble wild type protein or TTR T119M. The reactivity increased with oligomer formation and decreased as mature fibrils grow. After size exclusion chromatography (SEC) followed by sandwich ELISA and native immunoblotting, the mAb recognised two peaks (i) peak 1 present in acidified and in soluble variant proteins preparations with material above 146 KDa (ii) peak 2 only present in soluble L55P and S52P TTR preparations with material between 66 and 146 KDa. mAb CE11 may be a potential tool to survey therapeutical agents against TTR aggregation.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10829286","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 baseline polyneuropathy severity on patisiran treatment outcomes in the APOLLO trial.","authors":"Dianna Quan,&nbsp;Laura Obici,&nbsp;John L Berk,&nbsp;Yukio Ando,&nbsp;Emre Aldinc,&nbsp;Matthew T White,&nbsp;David Adams","doi":"10.1080/13506129.2022.2118043","DOIUrl":"https://doi.org/10.1080/13506129.2022.2118043","url":null,"abstract":"<p><strong>Objective: </strong>Assess how baseline polyneuropathy severity impacts response to patisiran regarding neurologic impairment and quality of life (QOL) in patients with hereditary transthyretin-mediated amyloidosis (ATTRv amyloidosis).</p><p><strong>Methods: </strong>This <i>post hoc</i> analysis grouped patients from the Phase 3 APOLLO study (<i>n</i> = 225) by baseline Neuropathy Impairment Score (NIS) into quartiles: 6-<31; 31-<57; 57-<85.5; 85.5-141.6. Neurologic impairment (modified NIS+7 [mNIS+7], NIS total score), disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test [10-MWT]), grip strength, and QOL (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN] questionnaire) were assessed.</p><p><strong>Results: </strong>Across all baseline NIS quartiles, patisiran improved several clinical markers of disease compared with placebo at 18 months. Patients in lower NIS quartiles, treated with patisiran earlier in the disease course, maintained better scores in mNIS+7, NIS total score, R-ODS, 10-MWT, grip strength, and Norfolk QOL-DN versus those in higher NIS quartiles, while placebo-treated patients experienced worsening of all functional measures after 18 months across all quartiles.</p><p><strong>Conclusions: </strong>Patisiran treatment improved neurologic function and QOL across a wide range of baseline polyneuropathy severities versus placebo. Timing of treatment initiation in patients with ATTRv amyloidosis remains critical for the preservation of function.(ClinicalTrials.gov number, NCT01960348).</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10835297","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":"Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial.","authors":"David Adams,&nbsp;Ivailo L Tournev,&nbsp;Mark S Taylor,&nbsp;Teresa Coelho,&nbsp;Violaine Planté-Bordeneuve,&nbsp;John L Berk,&nbsp;Alejandra González-Duarte,&nbsp;Julian D Gillmore,&nbsp;Soon-Chai Low,&nbsp;Yoshiki Sekijima,&nbsp;Laura Obici,&nbsp;Chongshu Chen,&nbsp;Prajakta Badri,&nbsp;Seth M Arum,&nbsp;John Vest,&nbsp;Michael Polydefkis","doi":"10.1080/13506129.2022.2091985","DOIUrl":"https://doi.org/10.1080/13506129.2022.2091985","url":null,"abstract":"<p><strong>Background: </strong>The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy.</p><p><strong>Methods: </strong>HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months.</p><p><strong>Results: </strong>HELIOS-A enrolled 164 patients (vutrisiran, <i>n</i> = 122; patisiran reference group, <i>n</i> = 42); external placebo, <i>n</i> = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (<i>p</i> = 3.54 × 10^-12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths.</p><p><strong>Conclusions: </strong>Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.</p><p><strong>Clinicaltrials.gov: </strong>NCT03759379.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416026","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":"Obituary.","authors":"Stefano Perlini","doi":"10.1080/13506129.2023.2168532","DOIUrl":"https://doi.org/10.1080/13506129.2023.2168532","url":null,"abstract":"","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10810114","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":"Identification of AL proteins from 10 λ-AL amyloidosis patients by mass spectrometry extracted from abdominal fat and heart tissue.","authors":"Julian Baur,&nbsp;Natalie Berghaus,&nbsp;Sarah Schreiner,&nbsp;Ute Hegenbart,&nbsp;Stefan O Schönland,&nbsp;Sebastian Wiese,&nbsp;Stefanie Huhn,&nbsp;Christian Haupt","doi":"10.1080/13506129.2022.2095618","DOIUrl":"https://doi.org/10.1080/13506129.2022.2095618","url":null,"abstract":"<p><strong>Background: </strong>Systemic AL amyloidosis arises from the misfolding of patient-specific immunoglobulin light chains (LCs). Potential drivers of LC amyloid formation are mutational changes and post-translational modifications (PTMs). However, little information is available on the exact primary structure of the AL proteins and their precursor LCs.</p><p><strong>Objective: </strong>We analyse the exact primary structure of AL proteins extracted from 10 <b>λ</b> AL amyloidosis patients and their corresponding precursor LCs.</p><p><strong>Materials and methods: </strong>By cDNA sequencing of the precursor LC genes in combination with mass spectrometry of the AL proteins, the exact primary structure and PTMs were determined. This information was used to analyse their biochemical properties.</p><p><strong>Results: </strong>All AL proteins comprise the V_L and a small part of the C_L with a common C-terminal truncation region. While all AL proteins retain the conserved native disulphide bond of the V_L, we found no evidence for presence of other common PTMs. The analysis of the biochemical properties revealed that the isoelectric point of the V_L is significantly increased due to introduced mutations.</p><p><strong>Conclusion: </strong>Our data imply that mutational changes influence the surface charge properties of the V_L and that common proteolytic processes are involved in the generation of the cleavage sites of AL proteins.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9080637","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}