A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils
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ABSTRACT:
PROVIDER: PRJEB81509 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13955406_1.fastq.gz | Fastqsanger.gz | |||
| ERR13955406_2.fastq.gz | Fastqsanger.gz | |||
| ERR13955407_1.fastq.gz | Fastqsanger.gz | |||
| ERR13955407_2.fastq.gz | Fastqsanger.gz | |||
| ERR13955408_1.fastq.gz | Fastqsanger.gz |
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Project description:Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis. The lack of reliable in vivo models hinders the study of the disease in its physiological context. We developped a transgenic mouse model producing high amounts of a human AL free light chain (LC). While mice exceptionnaly develop spontaneous AL amyloidosis and do not exhibit organ toxicity due to the circulating amyloidogenic LC, a single injection of amyloid fibrils, made up of the variable domain (VL) of the human LC, or soluble VL led to amyloid deposits, mainly in heart. The biochemical composition and the fragmentation pattern of the LC in the fibrils are highly similar to that of human AL fibrils, arguing for a conserved mechanism of amyloid fibrils formation. Amyloidosis positive mice also develop an early cardiac dysfunction, with increased NT-proBNP, diastolic dysfunction and remodeling of the extracellular matrix. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC initiate amyloid fibril formations in vivo. Accumulation of AL amyloid fibrils, rather than the soluble LC, drive the initial cardiac dysfunction. This model fills an important gap for research on AL amyloidosis and preclinical evaluation of new therapies.
2025-01-17 | GSE286368 | GEO
Project description:A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils
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Project description:Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (Vl) fit the fibril density. Despite Vl high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic Vl, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.
| S-EPMC6427027 | biostudies-literature
Project description:Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a β-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.
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Project description:Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity remain unclear. We identified gene expression changes correlating with human cardiac cell exposure to cardiomyopathy-associated AL LCs. We then confirmed these findings in a clinical dataset focusing on clinical parameters associated with pathways dysregulated at the gene expression level. Upon exposure to cardiomyopathy-associated AL LCs, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in global longitudinal strain (GLS) on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal interventricular septum diameter (IVSd) but abnormal cardiac biomarkers, suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.
2025-04-03 | GSE291559 | GEO
Project description:Light chain amyloidosis (AL) is a life-threatening plasma cell dyscrasia manifested by irreversible damage of multiple organs caused by monoclonal immunoglobulin light chain, production of pathogenic bone marrow plasma cells (BMPCs). Although AL is featured by both misfolding of monoclonal protein and plasma cell proliferation, the functional subclones and molecular mechanism of BMPCs in AL remain elusive. Also, inter-individual heterogeneities of AL determine the chemotherapy response and organ tropism of light chains, which require well-defined molecular subtypes. To address these, we conducted single-cell RNA sequencing (scRNA-seq) of BMPCs donated by patients with AL, patients with monoclonal gammopathy of undetermined significance (MGUS), and healthy controls. Single-cell transcriptome revealed a continuity of bone marrow plasma cell (BMPC) functional subclones, delineating DNA repair, cell proliferation, immunoglobulin production, etc., with the gradient of signaling entropy and immunoglobulin production. The amyloidosis-associated genes, such as the amyloid-beta binding Apolipoprotein E (APOE), Cystatin 3 (CST3), and Complement C1q A Chain (C1QA), were up-regulated in a subclone enriched in AL. The speculated light chain-producing subclones in AL up-regulated neutrophil degranulation pathways, transport to and modifications in Golgi apparatus, and asparagine N-linked protein glycosylation. Cyclin D1 (CCND1)hi AL, consisted of larger main subclones which highly expressed Bcl-2 complex and B-cell differentiation genes, was sensitive to venetoclax that targets Bcl-2. A major subset of CCND1low AL harbored larger carbohydrate-synthesizing subclone and up-regulated CCND2 and the amyloidosis-associated genes. Collectively, our results provided frontier insights into the functional subclones and molecular mechanism of BMPCs in AL, associated with amyloidosis, light chain production and venetoclax sensitivity, as knowledge for the future research on AL pathogenesis, AL subtypes and AL-specific therapies.
2022-06-01 | GSE188222 | GEO
Project description:AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5’ single cell RNA sequencing on 9 newly diagnosed, treatment naive AL amyloidosis patients and 8 healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of CD16 monocytes and subsets of CD4+ T cells in AL amyloidosis patients. We detected significant transcriptional changes broadly occurring among immune cells with increased interferon α and γ response and decreased TNF-α signaling. T and B cell receptor profiling revealed no overt clonal expansion of B or T cells in AL amyloidosis patients. However, we noted a disproportionate expansion of a distinct population of non-malignant plasma cells in AL amyloidosis patients. Finally, clonal AL amyloidosis plasma cells were identified based on their unique VDJ rearrangement and they showed increased expression of genes involved in proteostasis and antigen processing when compared to autologous, polyclonal plasma cells. Inter-patient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. Overall, this study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment, identifying transcriptional signatures that serve as candidates in early diagnosis in larger studies, and potential molecular targets for therapy.
2025-03-18 | GSE292189 | GEO
Project description:Immunoglobulin light chain (AL) amyloidosis is characterized by deposition of abnormal amyloid fibrils in multiple organs impairing their function. CD138-purified plasma cells producing these fibrils are investigated regarding chromosomal alterations by interphase fluorescence in situ hybridization (iFISH) using a multiple myeloma specific probe set for the IgH translocations as well as recurrent numerical aberrations. Aberrations genuine to AL amyloidosis cannot be detected due to the inherent limitation of this probe panel to known loci. We analyzed 118 AL amyloidosis patients by high-density copy number array to quantitatively detect genome-wide chromosomal imbalances. Most prevalent gains affected chromosomes 1q (37%), 9 (24%), 11q (24%), and 19 (16%). The most frequent deletion was monosomy 13 (28%) followed by partial deletions on 14q (21%), 16q (14%), and 13q (12%). The results were analyzed with respect to cytogenetic subgroups. In 88% of patients with translocation t(11;14) and concomitant gain of 11q22.3/11q23 detected by iFISH, the latter aberration was not due to trisomy of chromosome 11 but part of the unbalanced translocation der(14)t(11;14)(q13;q32) with breakpoint in the CCND1/MYEOV gene region. Partial loss of chromosomes 14q and 16q were significantly associated to patients with gain 1q. Our iFISH probe set is highly concordant with copy number results as it detects the most common cytogenetic aberrations present in AL amyloidosis. Beyond that, the probe panel is also the method of choice to detect translocations involving the IgH locus. In contrast to the results of our iFISH panel the frequency of hyperdiploidy detected by copy number array analysis is higher.
2017-03-29 | GSE89616 | GEO
Project description:We identified the protein in purified AL amyloid fibrils extracted from heart tissues from transgenic mice developing AL amyloidosis.
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