O-GlcNAc modification of the microtubule associated protein tau and α-synuclein can directly inhibit the formation of the associated amyloid fibers associated with major classes of neurodegenerative diseases. However, the mechanism(s) by which this posttranslational modification (PTM) inhibit amyloid aggregation are still murky. One hypothesis is that O-GlcNAc simply acts as a polyhydroxylated steric impediment to the formation of amyloid oligomers and fibers. Here, we begin to test this hypothesis by comparing the effects of O-GlcNAc to other similar monosaccharides—glucose, N-acetyl-galactosamine (GalNAc), or mannose—on α-synuclein amyloid formation. Interestingly, we find that this quite reasonable hypothesis is not entirely correct. More specifically, we used four types of biochemical and biophysical assays to discover that the different sugars display different effects on the inhibition of amyloid formation, despite only small differences between the structures of the monosaccharides. These results further support a more detailed investigation into the mechanism of amyloid inhibition by O-GlcNAc and has potential implications for the evolution of N-acetyl-glucosamine as the monosaccharide of choice for widespread intracellular glycosylation.

中文翻译：

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N-乙酰氨基葡萄糖与其他单糖的比较揭示了抑制 α-突触核蛋白聚集的结构差异

微管相关蛋白 tau 和 α-突触核蛋白的O -GlcNAc 修饰可以直接抑制与主要类别的神经退行性疾病相关的相关淀粉样蛋白纤维的形成。然而，这种翻译后修饰 (PTM) 抑制淀粉样蛋白聚集的机制仍不清楚。一种假设是O -GlcNAc 只是作为多羟基化的空间障碍物来阻碍淀粉样蛋白低聚物和纤维的形成。在这里，我们开始通过比较O -GlcNAc 与其他类似单糖（葡萄糖、N-乙酰半乳糖胺 (GalNAc) 或甘露糖 - 对 α-突触核蛋白淀粉样蛋白的形成。有趣的是，我们发现这个相当合理的假设并不完全正确。更具体地说，我们使用四种类型的生化和生物物理测定来发现不同的糖在抑制淀粉样蛋白形成方面表现出不同的效果，尽管单糖的结构之间只有很小的差异。这些结果进一步支持对O -GlcNAc抑制淀粉样蛋白的机制进行更详细的研究，并对N-乙酰氨基葡萄糖作为广泛细胞内糖基化选择的单糖的演变具有潜在的影响。