Document Detail


Specific glycosaminoglycans promote unseeded amyloid formation from beta2-microglobulin under physiological conditions.
MedLine Citation:
PMID:  17495865     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dialysis-related amyloidosis (DRA) is a complication of hemodialysis where beta2-microglobulin (beta2m) forms plaques mainly in cartilaginous tissues. The tissue-specific deposition, along with a known intransigence of pure beta2m to form fibrils in vitro at neutral pH in the absence of preformed fibrillar seeds, suggests a role for factors within cartilage in enhancing amyloid formation from this protein. To identify these factors, we determined the ability of a derivative lacking the N-terminal six amino acids found in ex vivo beta2m amyloid deposits to form amyloid fibrils at pH 7.4 in the absence of fibrillar seeds. We show that the addition of the glycosaminoglycans (GAGs) chrondroitin-4 or 6-sulfate to fibril growth assays results in the spontaneous generation of amyloid-like fibrils. By contrast, no fibrils are observed over the same time course in the presence of hyaluronic acid, a nonsulfated GAG that is abundant in cartilaginous joints. Based on the observation that hyaluronic acid has no effect on fibril stability, while chrondroitin-6-sulfate decreases the rate of fibril disassembly, we propose that the latter GAG enhances amyloid formation by stabilizing the rare fibrils that form spontaneously. This leads to the accumulation of beta2m in fibrillar deposits. Our data rationalize the joint-specific deposition of beta2m amyloid in DRA, suggesting mechanisms by which amyloid formation may be promoted.
Authors:
A J Borysik; I J Morten; S E Radford; E W Hewitt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-05-02
Journal Detail:
Title:  Kidney international     Volume:  72     ISSN:  0085-2538     ISO Abbreviation:  Kidney Int.     Publication Date:  2007 Jul 
Date Detail:
Created Date:  2007-07-12     Completed Date:  2007-09-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  174-81     Citation Subset:  IM    
Affiliation:
Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
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MeSH Terms
Descriptor/Qualifier:
Amyloid / biosynthesis,  chemistry
Amyloidosis / etiology*
Cartilage / metabolism
Chondroitin Sulfates / pharmacology
Glycosaminoglycans / pharmacology*
Humans
Hyaluronic Acid / pharmacology
Protein Conformation
beta 2-Microglobulin / metabolism*
Chemical
Reg. No./Substance:
0/Amyloid; 0/Glycosaminoglycans; 0/beta 2-Microglobulin; 9004-61-9/Hyaluronic Acid; 9007-28-7/Chondroitin Sulfates

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