Ena-DATASET-ICR-GM-17-12-2015-22:39:20:717-15 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001001861 | EGA |
REPOSITORIES: EGA
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Project description:Amyloidosis is a disorder characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis the most common form of amyloidosis can appear as a local disorder presented with mild symptoms or as a life threatening systemic disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this study, we investigated the protein composition of AL amyloid deposits isolated from human eyelid, conjunctival and orbital specimens. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were identified by liquid chromatography tandem mass spectrometry and subsequently quantified using the label-free mass spectrometry quantification method exponential modified Protein Abundance Index. Immunoglobulin light chain kappa or lambda was revealed to be the most predominant protein in the amyloid deposits. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provides high sensitivity and specificity of typing amyloidosis and may provide additional information on the pathology of amyloidosis.
2014-05-29 | PXD000743 | Pride
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:Amyloid deposition and neighboring tissue responses remain poorly understood. Twenty percent of patients with systemic light-chain amyloidosis (AL) have interstitial marrow amyloid containing clonal Ig light-chain fibrils and apolipoprotein chaperone proteins. We compared CD138-depleted aspirate mononuclear cells (MNC) from marrows of AL patients with (+MA) and without (-MA) interstitial amyloid by gene expression profiling (GEP) and single-cell RNA-sequencing (scRNA seq). GEP showed no differential expression of genes for proteolytic enzymes or apolipoproteins between the groups but +MA cases had significantly up-regulated erythroid genes involved in oxygen transport, including transmembrane and coiled-coil domain family 2 (TMCC2). In +MA marrows at the single-cell level, CD14+ monocytes were increased by 22%, granulocyte-monocyte progenitors decreased by 66%, and erythroid-megakaryocyte progenitors and early and late erythroid progenitors increased up to five-fold. Gene enrichment studies showed that in +MA marrows pathways for TNFα signaling, immune activation, monocyte hypoxia and erythropoiesis were significantly enriched. We also compared peripheral blood and marrow plasma by immunoprecipitation and immunoblot with respect to apolipoproteins and light chains in complex with the erythroid protein TMCC2, and by ELISA for marrow apolipoprotein E and J levels. Apolipoprotein J is strongly associated with light chains in blood and E is not, while in +MA marrow plasma J and E are strongly present in association with light chains. There is also significantly more apolipoprotein E and J in +MA marrow plasma. In summary, marrows with interstitial amyloid provide opportunities to study amyloid’s impact on cellular and regenerative activity and chaperone involvement in amyloid formation.
2023-12-01 | GSE239717 | GEO
Project description:The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well-described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of HLCs to the proteotoxicity of secreted TTR. To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We subsequently differentiated these lines into HLCs and performed single cell RNA sequencing (scRNAseq) via the Fluidigm C1 platform in an effort to identify a destabilized TTR-derived disease signature. Upon doing so, we identified a number of hepatic proteostasis factors (e.g. the unfolded protein response, UPR, as well as known and novel chaperone genes) whose expression correlates with the production destabilized TTR production.
2020-07-01 | GSE153541 | GEO
Project description:Exercise interventions are beneficial for reducing the risk of age-related diseases, including amyloidosis, but the underlying molecular links remain unelucidated. Here, we investigated the protective role of interval exercise training in a mouse model of age-related systemic apolipoprotein A-II amyloidosis (AApoAII) and elucidated potential mechanisms. Mice subjected to sixteen weeks of exercise improved whole-body physiologic functions and exhibited substantial inhibition of amyloidosis, particularly in the liver and spleen. Exercise activated the hepatic p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway and the downstream transcription factor tumor suppressor p53. This activation resulted in elevated expression and phosphorylation of heat shock protein beta-1 (HSPB1), a chaperone that defends against protein aggregation. In the amyloidosis-induced mice, the hepatic p38 MAPK-related adaptive responses were additively enhanced by exercise. We observed that with exercise, greatly increased amounts of phosphorylated HSPB1 accumulated at amyloid deposition areas, which we suspect to inhibit amyloid fibril formation. Collectively, our findings conclude exercise-activated, specific chaperone prevention of amyloidosis, and suggest that exercise may amplify intracellular stress-related protective adaptation pathways against age-associated disorders such as amyloidosis.
2022-03-04 | GSE192521 | GEO
Project description:Genomic profiling in amyloid light-chain amyloidosis reveals mutation profiles associated with overall survival Raw sequence reads
| PRJNA545879 | ENA
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:Amyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.
2022-10-03 | PXD024119 | Pride