Cell damage in light chain amyloidosis fibril internalization, toxicity and cell-mediated seeding

Marta Marin-Argany, Yi Lin, Pinaki Misra, Angela Williams, Jonathan S. Wall, Kyle G. Howell, Laura R. Elsbernd, Megan McClure, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)19813-19825
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number38
DOIs
StatePublished - Sep 16 2016

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Amyloidosis
Amyloid
Toxicity
Cells
Immunoglobulin Light Chains
Light
Cytotoxicity
Proteins
Amyloidogenic Proteins
Caspases
Cardiac Myocytes
Cell Communication
Image analysis
Apoptosis
Elongation
Assays
Agglomeration
Protein Aggregates

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cell damage in light chain amyloidosis fibril internalization, toxicity and cell-mediated seeding. / Marin-Argany, Marta; Lin, Yi; Misra, Pinaki; Williams, Angela; Wall, Jonathan S.; Howell, Kyle G.; Elsbernd, Laura R.; McClure, Megan; Ramirez-Alvarado, Marina.

In: Journal of Biological Chemistry, Vol. 291, No. 38, 16.09.2016, p. 19813-19825.

Research output: Contribution to journalArticle

Marin-Argany, M, Lin, Y, Misra, P, Williams, A, Wall, JS, Howell, KG, Elsbernd, LR, McClure, M & Ramirez-Alvarado, M 2016, 'Cell damage in light chain amyloidosis fibril internalization, toxicity and cell-mediated seeding', Journal of Biological Chemistry, vol. 291, no. 38, pp. 19813-19825. https://doi.org/10.1074/jbc.M116.736736
Marin-Argany, Marta ; Lin, Yi ; Misra, Pinaki ; Williams, Angela ; Wall, Jonathan S. ; Howell, Kyle G. ; Elsbernd, Laura R. ; McClure, Megan ; Ramirez-Alvarado, Marina. / Cell damage in light chain amyloidosis fibril internalization, toxicity and cell-mediated seeding. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 38. pp. 19813-19825.
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