Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease.
Quantitative proteomics identifies altered O-GlcNAcylation of structural, synaptic and memory-associated proteins in Alzheimer's disease.
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DOI：
10.1002/path.4929
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Liu T
中科院分区：
文献类型：
--
作者：
Wang S;Yang F;Petyuk VA;Shukla AK;Monroe ME;Gritsenko MA;Rodland KD;Smith RD;Qian WJ;Gong CX;Liu T
O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）的蛋白质修饰是散发性阿尔茨海默病发病机制中的一个重要因素，然而，由于其低化学计量和不稳定的性质，在蛋白质组水平上对这种重要蛋白质翻译后修饰的详细分子表征具有高度挑战性。在这里，我们报告了最全面的，定量的蛋白质组学分析的蛋白质O-GlcNAc酰化在死后的人脑组织与阿尔茨海默病，使用同量异序串联质量标签标记，化学酶光裂解富集和液相色谱质谱联用。从人脑中的530种蛋白质中鉴定出总共1，850种覆盖1，094个O-GlcNAc化位点的O-GlcNAc肽。与对照组相比，阿尔茨海默病脑中覆盖81种蛋白质的131种O-GlcNAc肽发生了改变（q <0.05）。此外，O-GlcNAc肽丰度的改变可能更多地归因于O-GlcNAc化水平而不是蛋白质水平的变化。改变的O-GlcNAc酰化蛋白属于几种结构和功能类别，包括突触蛋白、细胞骨架蛋白和记忆相关蛋白。这些发现表明，多种脑蛋白的O-GlcNAc化的失调可能参与了散发性阿尔茨海默病的发展。
Protein modification by O-linked beta-N-acetylglucosamine (O-GlcNAc) is emerging as an important factor in the pathogenesis of sporadic Alzheimer’s disease, however detailed molecular characterization of this important protein posttranslational modification at proteome level has been highly challenging, due to its low stoichiometry and labile nature. Herein we report the most comprehensive, quantitative proteomics analysis for protein O-GlcNAcylation in post-mortem human brain tissues with and without Alzheimer’s disease using isobaric tandem mass tags labeling, chemoenzymatic photocleavage enrichment and liquid chromatography coupled to mass spectrometry. A total of 1,850 O-GlcNAc peptides covering 1,094 O-GlcNAcylation sites were identified from 530 proteins in the human brain. One hundred and thirty one O-GlcNAc peptides covering 81 proteins were altered in Alzheimer’s brain as compared to controls (q <0.05). Moreover, alteration of O-GlcNAc peptide abundance could be attributed more to O-GlcNAcylation level than to protein level changes. The altered O-GlcNAcylated proteins belong to several structural and functional categories, including synaptic proteins, cytoskeleton proteins and memory-associated proteins. These findings suggest that dysregulation of O-GlcNAcylation of multiple brain proteins may be involved in the development of sporadic Alzheimer’s disease.
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1073/pnas.1200425109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Alfaro, Joshua F.;Gong, Cheng-Xin;Smith, Richard D.
通讯作者：
Smith, Richard D.
影响因子：
64.5
作者：
Huang Y;Mucke L
通讯作者：
Mucke L
影响因子：
14.9
作者：
Hornbeck PV;Zhang B;Murray B;Kornhauser JM;Latham V;Skrzypek E
通讯作者：
Skrzypek E
影响因子：
3.1
作者：
Monroe, Matthew E.;Shaw, Jason L.;Smith, Richard D.
通讯作者：
Smith, Richard D.