A Glycine Zipper Motif Mediates the Formation of Toxic Beta-Amyloid Oligomers in Vitro and in Vivo

Resource type
Date created
2011
Authors/Contributors
Abstract
Background: The b-amyloid peptide (Ab) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that hasbeen proposed to form a “glycine zipper” that drives the formation of toxic Ab oligomers. We have tested thishypothesis by examining the toxicity of Ab 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 Ab toxicity in all models tested, as measuredby cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiplemodels that Ab Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycinezipper formation blocks assembly of toxic Ab oligomers. To test this model rigorously, we engineered second sitesubstitutions in Ab predicted by the glycine zipper model to compensate for the Gly37Leu substitution andexpressed these in C. elegans. We show that these second site substitutions restore in vivo Abtoxicity, furthersupporting the glycine zipper model.Conclusions: Our structure/function studies support the view that the glycine zipper motif present in the Cterminalportion of Ab plays an important role in the formation of toxic Ab oligomers. Compounds designed tointerfere specifically with formation of the glycine zipper could have therapeutic potential.
Document
Published as
Fonte et al. Molecular Neurodegeneration 2011, 6:61
http://www.molecularneurodegeneration.com/content/6/1/61
Publication title
Molecular Neurodegeneration
Document title
A Glycine Zipper Motif Mediates the Formation of Toxic Beta-Amyloid Oligomers in Vitro and in Vivo
Date
2011
Volume
6
Issue
61
Copyright statement
Copyright is held by the author(s).
Permissions
You are free to copy, distribute and transmit this work under the following conditions: You must give attribution to the work (but not in any way that suggests that the author endorses you or your use of the work); You may not use this work for commercial purposes.
Scholarly level
Peer reviewed?
Yes
Language
Member of collection
Attachment Size
1750-1326-6-61.pdf 8.36 MB