Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA.
Mol Neurodegener. 2011 Aug 23;6(1):61. doi: 10.1186/1750-1326-6-61.
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.
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.
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.
β-淀粉样肽（Aβ）在其C末端区域含有一个Gly-XXX-Gly-XXX-Gly基序，有人提出该基序可形成驱动有毒Aβ寡聚体形成的“甘氨酸拉链”。我们通过使用神经元细胞系、原代神经元和转基因秀丽隐杆线虫模型，检测含有该基序替代物的Aβ变体的毒性，对这一假说进行了验证。
我们发现，通过细胞功能障碍、细胞死亡、突触改变或tau蛋白磷酸化来衡量，Gly37Leu替代在所有测试模型中均显著降低了Aβ毒性。我们还在多个模型中证明，Aβ Gly37Leu实际上具有抗毒性，从而支持了干扰甘氨酸拉链形成可阻止有毒Aβ寡聚体组装的假说。为了严格验证该模型，我们在甘氨酸拉链模型预测的Aβ中设计了第二位点替代，以补偿Gly37Leu替代，并在秀丽隐杆线虫中表达这些替代物。我们表明，这些第二位点替代可恢复体内Aβ毒性，进一步支持了甘氨酸拉链模型。
我们的结构/功能研究支持这样一种观点，即Aβ C末端部分存在的甘氨酸拉链基序在有毒Aβ寡聚体的形成中起重要作用。设计用于特异性干扰甘氨酸拉链形成的化合物可能具有治疗潜力。
