Cell Damage in Light Chain Amyloidosis

Light chain (AL) amyloidosis is an incurable human disease characterized by the misfolding, aggregation, and systemic deposition of amyloid composed of immunoglobulin light chains (LC). This work describes our studies on potential mechanisms of AL cytotoxicity. We have studied the internalization of AL soluble proteins and amyloid fibrils into human AC16 cardiomyocytes by using real time live cell image analysis. Our results show how external amyloid aggregates rapidly surround the cells and act as a recruitment point for soluble protein, triggering the amyloid fibril elongation. Soluble protein and external aggregates are internalized into AC16 cells via macropinocytosis. AL amyloid fibrils are shown to be highly cytotoxic at low concentrations. Additionally, caspase assays revealed soluble protein induces apoptosis, demonstrating different cytotoxic mechanisms between soluble protein and amyloid aggregates. This study emphasizes the complex immunoglobulin light chain-cell interactions that result in fibril internalization, protein recruitment, and cytotoxicity that may occur in AL amyloidosis.

• Publication year

  2016

• Venue

  Journal of Biological Chemistry

• Publication date

  2016-07-26

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M116.736736PMID 27462073PMCID PMC5025671
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Recruitment of Light Chains by Homologous and Heterologous Fibrils Shows Distinctive Kinetic and Conformational Specificity.

  2016cited by this paper
• Amyloid Formation in Human Islets Is Enhanced by Heparin and Inhibited by Heparinase

  2015cited by this paper
• Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

  2015cited by this paper
• Thermodynamic and fibril formation studies of full length immunoglobulin light chain AL-09 and its germline protein using scan rate dependent thermal unfolding.

  2015cited by this paper
• The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases

  2015cited by this paper
• Arf6 controls beta-amyloid production by regulating macropinocytosis of the Amyloid Precursor Protein to lysosomes

  2015cited by this paper
• Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity

  2014cited by this paper
• Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms

  2014cited by this paper
• Lysosomal dysfunction and impaired autophagy underlie the pathogenesis of amyloidogenic light chain-mediated cardiotoxicity

  2014cited by this paper
• Thermal Stability Threshold for Amyloid Formation in Light Chain Amyloidosis

  2013cited by this paper
• Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds

  2013cited by this paper
• Role of mutations in the cellular internalization of amyloidogenic light chains into cardiomyocytes

  2013cited by this paper
• Intracellular seeded aggregation of mutant Cu,Zn‐superoxide dismutase associated with amyotrophic lateral sclerosis

  2013cited by this paper
• Molecular structure of β-amyloid fibrils in Alzheimer's disease brain tissue.

  2013cited by this paper
• Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

  2013cited by this paper
• Cross-Seeding of Misfolded Proteins: Implications for Etiology and Pathogenesis of Protein Misfolding Diseases

  2013cited by this paper
• Extracellular Monomeric Tau Protein Is Sufficient to Initiate the Spread of Tau Protein Pathology*

  2013cited by this paper
• Roles for actin assembly in endocytosis.

  2012cited by this paper
• Tyrosine Residues Mediate Fibril Formation in a Dynamic Light Chain Dimer Interface

  2012cited by this paper
• Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity.

  2012cited by this paper
• Laser microdissection and mass spectrometry–based proteomics aids the diagnosis and typing of renal amyloidosis

  2012cited by this paper
• Molecular Structure of Amyloid Fibrils Controls the Relationship between Fibrillar Size and Toxicity

  2011cited by this paper
• Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis

  2011cited by this paper
• Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells

  2011cited by this paper
• In situ measurements of the formation and morphology of intracellular β-amyloid fibrils by super-resolution fluorescence imaging.

  2011cited by this paper
• Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score.

  2011cited by this paper
• Prion-like mechanisms in neurodegenerative diseases

  2010cited by this paper
• Cytotoxicity of amyloidogenic immunoglobulin light chains in cell culture

  2010cited by this paper
• Amyloid in endomyocardial biopsies

  2010cited by this paper
• Fibril fragmentation in amyloid assembly and cytotoxicity

  2010cited by this paper
• The Dynamin Inhibitors MiTMAB and OcTMAB Induce Cytokinesis Failure and Inhibit Cell Proliferation in Human Cancer Cells

  2010cited by this paper
• Molecular mechanism of Thioflavin-T binding to amyloid fibrils.

  2010cited by this paper
• Comparison of amyloid fibril formation by two closely related immunoglobulin light chain variable domains

  2010cited by this paper
• Amyloidogenic light chains induce cardiomyocyte contractile dysfunction and apoptosis via a non-canonical p38α MAPK pathway

  2010cited by this paper
• The critical role of the constant region in thermal stability and aggregation of amyloidogenic immunoglobulin light chain.

  2010cited by this paper
• Branching in amyloid fibril growth.

  2009cited by this paper
• Fibril Fragmentation Enhances Amyloid Cytotoxicity*♦

  2009cited by this paper
• Light chain amyloidosis - current findings and future prospects.

  2009cited by this paper
• Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens.

  2009cited by this paper
• Defining Macropinocytosis

  2009cited by this paper
• Amyloidogenic and Associated Proteins in Systemic Amyloidosis Proteome of Adipose Tissue*S

  2008cited by this paper
• Structural Classification of Toxic Amyloid Oligomers*

  2008cited by this paper
• Altered Dimer Interface Decreases Stability in an Amyloidogenic Protein*

  2008cited by this paper
• Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

  2008cited by this paper
• Use of dynasore, the small molecule inhibitor of dynamin, in the regulation of endocytosis.

  2008cited by this paper
• Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways.

  2007cited by this paper
• Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide

  2007cited by this paper
• Myristyl Trimethyl Ammonium Bromide and Octadecyl Trimethyl Ammonium Bromide Are Surface-Active Small Molecule Dynamin Inhibitors that Block Endocytosis Mediated by Dynamin I or Dynamin II

  2007cited by this paper
• HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway.

  2007cited by this paper
• Acid wash in determining cellular uptake of Fab/cell-permeating peptide conjugates.

  2007cited by this paper
• Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts.

  2006cited by this paper
• Dynasore, a cell-permeable inhibitor of dynamin.

  2006cited by this paper
• Inhibition of dynamin completely blocks compensatory synaptic vesicle endocytosis

  2006cited by this paper
• Kinetics and thermodynamics of amyloid assembly using a high-performance liquid chromatography-based sedimentation assay.

  2006cited by this paper
• Mechanism of thioflavin T binding to amyloid fibrils.

  2005cited by this paper
• Cellular response of cardiac fibroblasts to amyloidogenic light chains.

  2005cited by this paper
• Diagnosis and Management of the Cardiac Amyloidoses

  2005cited by this paper
• Novel cell lines derived from adult human ventricular cardiomyocytes.

  2005cited by this paper
• Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns

  2004cited by this paper
• Human Amyloidogenic Light Chains Directly Impair Cardiomyocyte Function Through an Increase in Cellular Oxidant Stress

  2004cited by this paper
• Structural basis of light chain amyloidogenicity: comparison of the thermodynamic properties, fibrillogenic potential and tertiary structural features of four Vλ6 proteins

  2004cited by this paper
• Heparan Sulfate Proteoglycans Mediate the Invasion of Cardiomyocytes by Trypanosoma cruzi

  2003cited by this paper
• Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis

  2003cited by this paper
• Transmissibility of systemic amyloidosis by a prion-like mechanism

  2002cited by this paper
• Dynamin 2 Is Required for Phagocytosis in Macrophages

  1999cited by this paper
• Thermodynamic instability of human lambda 6 light chains: correlation with fibrillogenicity.

  1999cited by this paper
• Fragments of the constant region of immunoglobulin light chains are constituents of AL-amyloid proteins.

  1998cited by this paper
• Macropinosome maturation and fusion with tubular lysosomes in macrophages

  1993cited by this paper
• Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavin T1.

  1989cited by this paper
• PHYSICAL AND CHEMICAL PROPERTIES OF AMYLOID FIBERS II. ISOLATION OF A UNIQUE PROTEIN CONSTITUTING THE MAJOR COMPONENT FROM HUMAN SPLENIC AMYLOID FIBRIL CONCENTRATES

  1969cited by this paper
• Fibril fragmentation in amyloid assembly and cytotoxicity When size matters

  year unknowncited by this paper

• Incidence and Predictors of Appropriate Implantable Cardioverter-Defibrillator Therapy in Light Chain Cardiac Amyloidosis.

  2026cites this paper
• Genetic and structural aspects of amyloid diseases.

  2025cites this paper
• In vitro and in vivo disease models of cardiac amyloidosis: progress, pitfalls, and potential

  2025cites this paper
• Echocardiographic Phenotypic Differences between Light Chain and Transthyretin Cardiac Amyloid and Relation to Outcome.

  2025cites this paper
• Clonal plasma cell features in light chain amyloidosis are associated with depth and timing of cardiac response independent of hematologic response

  2025cites this paper
• The molecular landscape of AL amyloidosis

  2025cites this paper
• Whole tissue proteomic analyses of cardiac ATTR and AL unveil mechanisms of tissue damage

  2025cites this paper
• Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition

  2025cites this paper
• Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us?

  2024cites this paper
• Parametric mapping using cardiovascular magnetic resonance for the differentiation of light chain amyloidosis and transthyretin-related amyloidosis.

  2024cites this paper
• Native State Stabilization of Amyloidogenic Proteins by Kinetic Stabilizers: Inhibition of Protein Aggregation and Clinical Relevance

  2024cites this paper
• 2024 Australia-New Zealand Expert Consensus Statement on Cardiac Amyloidosis.

  2024cites this paper
• The diagnostic and therapeutic implications of phenocopies and mimics of Hypertrophic Cardiomyopathy.

  2024cites this paper
• gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity

  2024cites this paper
• Arrhythmias and Device Therapies in Cardiac Amyloidosis

  2024cites this paper
• Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases

  2024cites this paper
• Cardiac Troponin in Patients With Light Chain and Transthyretin Cardiac Amyloidosis

  2024cites this paper
• PRIMARY SYSTEMIC AMYLOIDOSIS: A BRIEF OVERVIEW.

  2024cites this paper
• Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease

  2024cites this paper
• Cardiac Amyloidosis: State-of-the-Art Review in Molecular Pathology

  2024cites this paper
• The myocardial function index (MFI): An integrated measure of cardiac function in AL-cardiomyopathy

  2024cites this paper
• The Pathophysiological and Therapeutic Implications of Cardiac Light-Chain Amyloidosis Compared With Transthyretin Amyloidosis.

  2024cites this paper
• Successes in translation

  2024cites this paper
• Renale Amyloidosen

  2024cites this paper
• Hearts are NOT Made to Be Broken: Expert Opinion on Amyloid Light-Chain Cardiac Amyloidosis

  2023cites this paper
• Amyloid deposition through endocytosis in vascular endothelial cells.

  2023cites this paper
• Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation

  2023cites this paper
• Role of the mechanisms for antibody repertoire diversification in monoclonal light chain deposition disorders: when a friend becomes foe

  2023cites this paper
• Pharmacological stabilization of the native state of full-length immunoglobulin light chains to treat light chain amyloidosis.

  2023cites this paper
• Impaired Extracellular Proteostasis in Patients with Heart Failure.

  2023cites this paper
• Physiology, Diagnosis and Treatment of Cardiac Light Chain Amyloidosis

  2022cites this paper
• Cu(II) Binding Increases the Soluble Toxicity of Amyloidogenic Light Chains

  2022cites this paper
• Antibodies gone bad – the molecular mechanism of light chain amyloidosis

  2022cites this paper
• High-avidity binding drives nucleation of amyloidogenic transthyretin monomer

  2022cites this paper
• Supportive Care and Symptom Management for Patients With Immunoglobulin Light Chain (AL) Amyloidosis

  2022cites this paper
• Targeting Amyloid Fibrils by Passive Immunotherapy in Systemic Amyloidosis

  2022cites this paper
• Understanding AL amyloidosis with a little help from in vivo models

  2022influential citation
• Cardiac amyloidosis—An underdiagnosed cause of heart failure: A case report and review of literature

  2022cites this paper
• Early events in light chain aggregation at physiological pH reveal new insights on assembly, stability, and aggregate dissociation

  2021cites this paper
• How I Treat AL Amyloidosis.

  2021cites this paper
• Ventricular tachyarrhythmias and sudden cardiac death in light‐chain amyloidosis: a clash of cardio‐toxicities?

  2021cites this paper
• Glomerulopathic Light Chain-Mesangial Cell Interactions: Sortilin-Related Receptor (SORL1) and Signaling

  2021cites this paper
• Computational investigation of the binding of a designed peptide to λ light chain amyloid fibril.

  2021cites this paper
• Future Perspectives

  2020cites this paper
• The Influence of the Mixed DPC:SDS Micelle on the Structure and Oligomerization Process of the Human Cystatin C

  2020cites this paper
• Protein Aggregation, Related Pathologies, and Aging

  2020cites this paper
• Domain interactions determine the amyloidogenicity of antibody light chain mutants.

  2020cites this paper
• Fatal amyloid formation in a patient’s antibody light chain is caused by a single point mutation

  2020cites this paper
• AL amyloidosis: advances in diagnosis and management

  2019cites this paper
• Mechanistic Insights into the Early Events in the Aggregation of Immunoglobulin Light Chains.

  2019cites this paper
• Inherent biophysical properties modulate the toxicity of soluble amyloidogenic light chains.

  2019cites this paper
• Light chain amyloidosis induced inflammatory changes in cardiomyocytes and adipose-derived mesenchymal stromal cells

  2019cites this paper
• Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain (AL) amyloidosis patient.

  2019cites this paper
• Unfolding Cardiac Amyloidosis - From Pathophysiology to Cure.

  2019cites this paper
• Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

  2018cites this paper
• Isolation and purification of recombinant immunoglobulin light chain variable domains from the periplasmic space of Escherichia coli

  2018cites this paper
• Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

  2018cites this paper
• Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy

  2018cites this paper
• Systemic immunoglobulin light chain amyloidosis

  2018cites this paper
• Assays for Light Chain Amyloidosis Formation and Cytotoxicity.

  2018cites this paper
• Recent advances in understanding and treating immunoglobulin light chain amyloidosis

  2018cites this paper
• Immunoglobulin light chain amyloid aggregation.

  2018cites this paper
• Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

  2018cites this paper
• Mesenchymal stromal cells protect human cardiomyocytes from amyloid fibril damage.

  2017cites this paper
• Immunoglobulin Light Chains Form an Extensive and Highly Ordered Fibril Involving the N- and C-Termini

  2017cites this paper
• Contribution of human smooth muscle cells to amyloid angiopathy in AL (light-chain) amyloidosis

  2017cites this paper
• Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity

  2017cites this paper
• Proteotoxicity in cardiac amyloidosis: amyloidogenic light chains affect the levels of intracellular proteins in human heart cells

  2017cites this paper
• MAK33 antibody light chain amyloid fibrils are similar to oligomeric precursors

  2017cites this paper
• AL amyloidosis: from molecular mechanisms to targeted therapies.

  2017cites this paper
• Differences in Protein Concentration Dependence for Nucleation and Elongation in Light Chain Amyloid Formation.

  2017cites this paper
• Phase 2 trial of daily, oral epigallocatechin gallate in patients with light-chain amyloidosis

  2017cites this paper
• Journal Pre-proof The diagnostic and therapeutic implications of phenocopies and mimics of Hypertrophic Cardiomyopathy

  year unknowncites this paper