Sequestration of the A beta Peptide Prevents Toxicity and Promotes Degradation In Vivo
2010 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 8, no 3, e1000334- p.Article in journal (Refereed) Published
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 (A beta) peptide by using a small engineered binding protein (Z(A beta 3)) that binds with nanomolar affinity to A beta, completely sequestering the aggregation-prone regions of the peptide and preventing its aggregation. Co-expression of Z(A beta 3) in the brains of Drosophila melanogaster expressing either A beta(42) or the aggressive familial Alzheimer's disease (AD) associated E22G variant of A beta(42) abolishes their neurotoxic effects. Biochemical analysis indicates that monomer A beta binding results in degradation of the peptide in vivo. Complementary biophysical studies emphasize the dynamic nature of A beta aggregation and reveal that Z(A beta 3) not only inhibits the initial association of A beta 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.
Place, publisher, year, edition, pages
2010. Vol. 8, no 3, e1000334- p.
ALZHEIMERS-DISEASE, DROSOPHILA MODEL, PROTEIN, LIGANDS, BINDING, NEURODEGENERATION, OLIGOMERS, PATHWAYS, DISTINCT, PLAQUES
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:kth:diva-27565DOI: 10.1371/journal.pbio.1000334ISI: 000278125400012ScopusID: 2-s2.0-77950579610OAI: oai:DiVA.org:kth-27565DiVA: diva2:378248
QC 201012152010-12-152010-12-132010-12-15Bibliographically approved