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Specific glycosaminoglycans promote unseeded amyloid formation from beta2-microglobulin under physiological conditions.
Borysik, A J; Morten, I J; Radford, S E; Hewitt, E W.
Afiliación
  • Borysik AJ; Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK.
Kidney Int ; 72(2): 174-81, 2007 Jul.
Article en En | MEDLINE | ID: mdl-17495865
ABSTRACT
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.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglobulina beta-2 / Glicosaminoglicanos / Amiloidosis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Kidney Int Año: 2007 Tipo del documento: Article País de afiliación: Reino Unido
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Microglobulina beta-2 / Glicosaminoglicanos / Amiloidosis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Kidney Int Año: 2007 Tipo del documento: Article País de afiliación: Reino Unido
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