A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

Molecular Neurodegeneration

Christopher D Link⁵  Gretchen H Stein¹  Michael A Silverman³  Emily Y Fan³  Natalie Dingwell³  Jordi Magrane⁴  Pascale Lacor²  Patrick Gonzales⁶  Christine M Roberts⁶  Vishantie Dostal⁶  Virginia Fonte⁶ 

[1] Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309, USA;Neurobiology and Physiology Department, Northwestern University, Evanston, IL, 60208, USA;Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada;Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA;Integrative Physiology, University of Colorado, Boulder, CO 80309, USA;Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA

关键词: glycine motif;    pore-forming toxin;    C. elegans;    Alzheimer's disease;   

Others  :  865652
DOI  :  10.1186/1750-1326-6-61

 received in 2011-06-10, accepted in 2011-08-23,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Fonte et al; licensee BioMed Central Ltd.

【 图 表 】

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