A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo.
ABSTRACT: BACKGROUND: The β-amyloid peptide (Aβ) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a "glycine zipper" that drives the formation of toxic Aβ oligomers. We have tested this hypothesis by examining the toxicity of Aβ variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model. RESULTS: We found that a Gly37Leu substitution dramatically reduced Aβ toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aβ Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aβ oligomers. To test this model rigorously, we engineered second site substitutions in Aβ predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo Aβtoxicity, further supporting the glycine zipper model. CONCLUSIONS: Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Aβ plays an important role in the formation of toxic Aβ oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.[1]References
- A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo. Fonte, V., Dostal, V., Roberts, C.M., Gonzales, P., Lacor, P., Magrane, J., Dingwell, N., Fan, E.Y., Silverman, M.A., Stein, G.H., Link, C.D. Mol. Neurodegener (2011) [Pubmed]
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