Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1234143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32636974_1.fastq.gz | Fastqsanger.gz | |||
| SRR32636974_2.fastq.gz | Fastqsanger.gz | |||
| SRR32636975_1.fastq.gz | Fastqsanger.gz | |||
| SRR32636975_2.fastq.gz | Fastqsanger.gz | |||
| SRR32636976_1.fastq.gz | Fastqsanger.gz |
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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: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:Systemic ALys amyloidosis is a debilitating protein misfolding diseases that arises from the formation of amyloid fibrils from C-type lysozyme. We here present a 2.8 A cryo-electron microscopy structure of an amyloid fibril, which was isolated from the abdominal fat tissue of a patient who expressed the D87G variant of human lysozyme. We find that the fibril possesses a stable core that is formed by all 130 residues of the fibril precursor protein. There are four disulfide bonds in each fibril protein that connect the same residues as in the globularly folded protein. However, the conformation is fundamentally different in the fibril and in native lysozyme, demonstrating the need of protein unfolding. The position of the mutant residue within the fibril structure implies that the role of this mutation includes the stabilization of the pathogenic fibril structure.
2024-10-21 | MSV000096142 | MassIVE
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: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: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:Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N- and C-termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N- and C-terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LCs’ variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling, by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LCs processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, they show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.
2020-10-15 | PXD020858 | Pride
Project description:A mouse model of cardiac AL amyloidosis unveils mechanisms of tissue accumulation and toxicity of amyloid fibrils
2025-01-17 | PXD059046 | Pride
Project description:Crespo2012 - Kinetics of Amyloid Fibril
Formation
This model is described in the article:
A generic
crystallization-like model that describes the kinetics of
amyloid fibril formation.
Crespo R, Rocha FA, Damas AM,
Martins PM.
J. Biol. Chem. 2012 Aug; 287(36):
30585-30594
Abstract:
Associated with neurodegenerative disorders such as
Alzheimer, Parkinson, or prion diseases, the conversion of
soluble proteins into amyloid fibrils remains poorly
understood. Extensive "in vitro" measurements of protein
aggregation kinetics have been reported, but no consensus
mechanism has emerged until now. This contribution aims at
overcoming this gap by proposing a theoretically consistent
crystallization-like model (CLM) that is able to describe the
classic types of amyloid fibrillization kinetics identified in
our literature survey. Amyloid conversion represented as a
function of time is shown to follow different curve shapes,
ranging from sigmoidal to hyperbolic, according to the relative
importance of the nucleation and growth steps. Using the CLM,
apparently unrelated data are deconvoluted into generic
mechanistic information integrating the combined influence of
seeding, nucleation, growth, and fibril breakage events. It is
notable that this complex assembly of interdependent events is
ultimately reduced to a mathematically simple model, whose two
parameters can be determined by little more than visual
inspection. The good fitting results obtained for all cases
confirm the CLM as a good approximation to the generalized
underlying principle governing amyloid fibrillization. A
perspective is presented on possible applications of the CLM
during the development of new targets for amyloid disease
therapeutics.
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2024-09-02 | BIOMD0000000531 | BioModels
Project description:The accumulation of amyloid beta peptides in fibrils is prerequisite for
Alzheimers disease (AD). Our understanding of the proteins that promote Abeta fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts.
2023-06-29 | MSV000092311 | MassIVE