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.
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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.
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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.
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Project description:Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson's disease (PD), ?-synuclein (?-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of ?-syn with a cross-? structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-? sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-? structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-? structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of ?-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of ?-syn.
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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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Project description:we investigated the N-glycosylation of the amyloid fibrils extracted from the heart of a patient affected by AL amyloidosis, using a proteomic approach to evaluate indirectly the presence of glycans in immunoglobulin light chains.
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Project description:We investigated the N- and C-terminome of the LCs proteoforms in fibrils extracted from the hearts of a patient affected by AL amyloidosis, using a proteomic approach based on N- and C-terminal residues derivatization, followed by mapping of fragmentation sites on the structures of fibrillar LCs
2024-07-02 | PXD049301 | Pride
Project description:Systemic amyloidoses are characterized by the unrelenting deposition of autologous proteins as highly ordered fibrils in target organs. The ensuing, potentially fatal organ dysfunction is the result of the combined damage caused by the proteotoxic effect of prefibrillar species and by the cytotoxicity and the structural alterations produced by the amyloid fibrils. Current therapy is focused on eliminating the amyloid protein, thus extinguishing the amyloid cascade at its origin. While this approach may end the cell damage caused by prefibrillar aggregates and prevent further amyloid accumulation, the noxious effects of the amyloid fibrils persist and may hamper the recovery of organ function, which is the ultimate goal of therapy as it is necessary to improve the quality of life and extend survival. Preclinical studies indicate that the clearance of amyloid deposits can be accelerated by specific antibodies targeting amyloid fibrils that activate complement-mediated macrophages and giant cell phagocytosis, possibly promoting the recovery of organ function. Measuring the therapeutic effect of anti-amyloid agents is still a matter of research. In recent years, several monoclonal antibodies targeting amyloid deposits have been tested in clinical trials with mixed outcomes. Recent encouraging results from phase I/II trials, new anti-amyloid agents, and new antibody engineering offer hope that effective amyloid removal will be accomplished in the near future, accelerating organ recovery and improving quality of life and survival.
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