O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.
O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.
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DOI：
10.1038/nchem.2361
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发表时间：
2015-11
期刊：
影响因子：
21.8
通讯作者：
Pratt MR
中科院分区：
文献类型：
--
作者：
Marotta NP;Lin YH;Lewis YE;Ambroso MR;Zaro BW;Roth MT;Arnold DB;Langen R;Pratt MR
与神经退行性疾病相关的几种易于聚集的蛋白质可以被O-连接的N-乙酰基-葡萄糖胺（O-GlcNAc）在体内修饰。其中一种蛋白质，α-突触核蛋白，是一种与突触核蛋白病（包括帕金森病）相关的毒性聚集蛋白。然而，O-GlcNAc化对α-突触核蛋白的影响尚不清楚。在这里，我们使用合成蛋白质化学来产生未修饰的α-突触核蛋白和在生理相关的苏氨酸残基72处具有位点特异性O-GlcNAc修饰的α-突触核蛋白。我们发现，这种单一的修饰对α-突触核蛋白的聚集有显着的亚化学计量的构象效应，而不影响α-突触核蛋白的膜结合或弯曲性质。O-GlcNAc酰化还显示影响体外α-突触核蛋白的磷酸化，并阻断外源添加到培养物中的细胞中的α-突触核蛋白的毒性。这些结果表明，增加O-GlcNAc化可以减缓突触核蛋白病的进展，并进一步支持O-GlcNAc在预防蛋白质聚集中的一般功能。
Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating-protein associated with synucleinopathies, including Parkinson’s disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein bearing a site-specific O-GlcNAc modification at the physiologically-relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory-effect on α-synuclein aggregation, whilst not affecting the membrane binding or bending properties of α-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of α-synuclein in vitro and block the toxicity of α-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation.