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Plos Biology : Sequestration of the Ab Peptide Prevents Toxicity and Promotes Degradation in Vivo, Volume 8

By Guo, Ming

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Book Id: WPLBN0003940971
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Sequestration of the Ab Peptide Prevents Toxicity and Promotes Degradation in Vivo, Volume 8  
Author: Guo, Ming
Volume: Volume 8
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection, PLoS Biology
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Publication Date:
Publisher: Plos

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Guo, M. (n.d.). Plos Biology : Sequestration of the Ab Peptide Prevents Toxicity and Promotes Degradation in Vivo, Volume 8. Retrieved from http://netlibrary.net/


Description
Description : Protein aggregation, arising from the failure of the cell to regulate the synthesis or degradation of aggregation-prone proteins, underlies many neurodegenerative disorders. However, the balance between the synthesis, clearance, and assembly of misfolded proteins into neurotoxic aggregates remains poorly understood. Here we study the effects of modulating this balance for the amyloid-beta (Ab) peptide by using a small engineered binding protein (ZAb3) that binds with nanomolar affinity to Ab, completely sequestering the aggregation-prone regions of the peptide and preventing its aggregation. Co-expression of ZAb3 in the brains of Drosophila melanogaster expressing either Ab42 or the aggressive familial Alzheimer9s disease (AD) associated E22G variant of Ab42 abolishes their neurotoxic effects. Biochemical analysis indicates that monomer Ab binding results in degradation of the peptide in vivo. Complementary biophysical studies emphasize the dynamic nature of Ab aggregation and reveal that ZAb3 not only inhibits the initial association of Ab monomers into oligomers or fibrils, but also dissociates pre-formed oligomeric aggregates and, although very slowly, amyloid fibrils. Toxic effects of peptide aggregation in vivo can therefore be eliminated by sequestration of hydrophobic regions in monomeric peptides, even when these are extremely aggregation prone. Our studies also underline how a combination of in vivo and in vitro experiments provide mechanistic insight with regard to the relationship between protein aggregation and clearance and show that engineered binding proteins may provide powerful tools with which to address the physiological and pathological consequences of protein aggregation.

 

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