Glycosaminoglycan-modulated divergent aggregation of serum amyloid A

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Authors
Aguilera, J. Javier
Issue Date
2013-08
Type
Electronic thesis
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Language
ENG
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Chemistry
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Abstract
Overall, the results revealed that all GAGs served as a scaffold to accelerate the formation β-sheet species, to varying degrees. Three divergent aggregation pathways were identified, depending on the GAG involved. Remarkably, heparin exhibited a bifurcated mechanism that facilitated acceleration of SAA protofibrillar formation, but capped fibrillation, whereas chondroitin sulfate A (CSA) facilitated the formation of spherical oligomers of various sizes, but completely blocked SAA fibril formation. SDS-PAGE and glutaraldehyde cross-linking were combined to trap oligomeric-aggregated species that form during the GAG-mediated aggregation of SAA. Remarkably, the gels revealed that with the exception of heparosan, the GAGs, and especially CSA, significantly increased the rate of the previously observed auto-proteolytic degradation of SAA. The main fragment generated had a molecular weight of about 8 kDa and was more persistent for pathogenic SAA1.1, suggesting that GAGs may play a role in the proteolytic mechanism resulting in AA amyloid deposits. In conclusion, these studies prove as a useful start for further understanding the role of GAGs in AA amyloidosis and for exploring their potential therapeutic value.
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August 2013
School of Science
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Rensselaer Polytechnic Institute, Troy, NY
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