Aggregation of full-length immunoglobulin light chains from systemic light chain amyloidosis (AL) patients is remodeled by epigallocatechin-3-gallate

Kathrin Andrich, Ute Hegenbart, Christoph Kimmich, Niraja Kedia, Harold Robert (Bob) III Bergen, Stefan Schönland, Erich Wanker, Jan Bieschke

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Intervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo. We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from the urine of AL and MM patients. We quantified their thermodynamic stabilities and monitored their aggregation under physiological conditions by thioflavin T fluorescence, light scattering, SDS stability, and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ∼50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-β and α-synuclein.

Original languageEnglish (US)
Pages (from-to)2328-2344
Number of pages17
JournalJournal of Biological Chemistry
Volume292
Issue number6
DOIs
StatePublished - Feb 10 2017

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Immunoglobulin Light Chains
Amyloidosis
Agglomeration
Light
Amyloid
Multiple Myeloma
Kinetics
epigallocatechin gallate
Synucleins
Polyphenols
Atomic Force Microscopy
Amyloid Plaques
Oligomers
Disulfides
Dimers
Light scattering
Plasma Cells
Thermodynamics
Atomic force microscopy
Thermodynamic stability

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Aggregation of full-length immunoglobulin light chains from systemic light chain amyloidosis (AL) patients is remodeled by epigallocatechin-3-gallate. / Andrich, Kathrin; Hegenbart, Ute; Kimmich, Christoph; Kedia, Niraja; Bergen, Harold Robert (Bob) III; Schönland, Stefan; Wanker, Erich; Bieschke, Jan.

In: Journal of Biological Chemistry, Vol. 292, No. 6, 10.02.2017, p. 2328-2344.

Research output: Contribution to journalArticle

Andrich, Kathrin ; Hegenbart, Ute ; Kimmich, Christoph ; Kedia, Niraja ; Bergen, Harold Robert (Bob) III ; Schönland, Stefan ; Wanker, Erich ; Bieschke, Jan. / Aggregation of full-length immunoglobulin light chains from systemic light chain amyloidosis (AL) patients is remodeled by epigallocatechin-3-gallate. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 6. pp. 2328-2344.
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AU - Kedia, Niraja

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