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Aggregation modulators interfere with membrane interactions of beta2-microglobulin fibrils.

Sheynis, Tania, Friediger, Anat, Xue, Wei-Feng, Hellewell, Andrew L., Tipping, Kevin W, Hewitt, Eric W., Radford, Sheena E., Jelinek, Raz (2013) Aggregation modulators interfere with membrane interactions of beta2-microglobulin fibrils. Biophysical Journal, 105 (3). pp. 745-755. ISSN 0006-3495. (doi:10.1016/j.bpj.2013.06.015) (KAR id:35599)


Amyloid fibril accumulation is a pathological hallmark of several devastating disorders, including Alzheimer's disease, prion diseases, type II diabetes, and others. Although the molecular factors responsible for amyloid pathologies have not been deciphered, interactions of misfolded proteins with cell membranes appear to play important roles in these disorders. Despite increasing evidence for the involvement of membranes in amyloid-mediated cytotoxicity, the pursuit for therapeutic strategies has focused on preventing self-assembly of the proteins comprising the amyloid plaques. Here we present an investigation of the impact of fibrillation modulators upon membrane interactions of ?2-microglobulin (?2m) fibrils. The experiments reveal that polyphenols (epigallocatechin gallate, bromophenol blue, and resveratrol) and glycosaminoglycans (heparin and heparin disaccharide) differentially affect membrane interactions of ?2m fibrils measured by dye-release experiments, fluorescence anisotropy of labeled lipid, and confocal and cryo-electron microscopies. Interestingly, whereas epigallocatechin gallate and heparin prevent membrane damage as judged by these assays, the other compounds tested had little, or no, effect. The results suggest a new dimension to the biological impact of fibrillation modulators that involves interference with membrane interactions of amyloid species, adding to contemporary strategies for combating amyloid diseases that focus on disruption or remodeling of amyloid aggregates.

Item Type: Article
DOI/Identification number: 10.1016/j.bpj.2013.06.015
Subjects: Q Science > QC Physics
Q Science > QD Chemistry
Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Wei-Feng Xue
Date Deposited: 23 Oct 2013 13:58 UTC
Last Modified: 16 Nov 2021 10:12 UTC
Resource URI: (The current URI for this page, for reference purposes)

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