title: Cell Damage in Light Chain Amyloidosis: FIBRIL INTERNALIZATION, TOXICITY AND CELL-MEDIATED SEEDING.
abstract: 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.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and.
authors.forename: Marta
authors.identifier: 0000-0002-7356-3969
authors.initials: M
authors.lastname: Marin-Argany
authors.affiliation: the Division of Hematology, the Human Cell Therapy Lab, Division of Transfusion Medicine.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and.
authors.forename: Pinaki
authors.initials: P
authors.lastname: Misra
authors.affiliation: the Departments of Medicine and Radiology, the University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920.
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.affiliation: the Departments of Medicine and Radiology, the University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
authors.affiliation: the Department of Microscopy and the Cell Analysis Core Facility, and.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Howell
authors.affiliation: Immunology.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Elsbernd
authors.affiliation: the Department of Radiology, Mayo Clinic, Rochester, Minnesota 55905 and.
authors.forename: Megan
authors.initials: M
authors.lastname: McClure
authors.affiliation: From the Departments of Biochemistry and Molecular Biology and Immunology, ramirezalvarado.marina@mayo.edu.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism*; D010873:Pinocytosis; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains
keywords: amyloid; apoptosis; cardiomyocytes; cell internalization; endocytosis; fibril fragmentation; in vivo imaging; light chain amyloidosis; protein aggregation; toxicity