Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer's Disease.
Targeted Quantification of Detergent-Insoluble RNA-Binding Proteins in Human Brain Reveals Stage and Disease Specific Co-aggregation in Alzheimer's Disease.
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DOI：
10.3389/fnmol.2021.623659
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发表时间：
2021
影响因子：
4.8
通讯作者：
Seyfried NT
中科院分区：
文献类型：
--
作者：
Guo Q;Dammer EB;Zhou M;Kundinger SR;Gearing M;Lah JJ;Levey AI;Shulman JM;Seyfried NT
核心剪接体和相关的RNA结合蛋白聚集在阿尔茨海默病(AD)的大脑中，甚至在疾病的早期无症状阶段(AsymAD)也是如此。为了评估阿尔茨海默病(AD)中核糖核酸结合蛋白聚集的特异性，我们开发了一种靶向质谱学方法来定量检测来自对照组、AsymAD、AD和帕金森病(PD)脑的洗涤剂不溶部分中与其他病理蛋白包括tau和淀粉样β蛋白(Aβ)的广泛类别的RNA结合蛋白。不同疾病组中特定不溶性核糖核酸结合蛋白的相对水平与A、β和tau聚集体的积累相关。RNA结合蛋白，包括与U1-70K的碱性-酸性二肽重复序列同源的剪接因子，优先聚集在AsymAD和AD中。相比之下，与AsymAD和AD组相比，PD脑团聚体中许多RNA结合蛋白相对匮乏。相关网络分析解析了29个不同的共聚集蛋白质模块，包括与剪接体组装、核斑点和RNA剪接相关的模块。与剪接体组装和核斑点相关的模块显示，AsymAD和AD脑中不溶性RBPs的阶段特异性浓缩，而RNA剪接模块在PD中特异性减少。总的来说，这项工作识别了一类RNA结合蛋白，这些蛋白在我们检查的特定神经退行性疾病中明显地共同聚集在洗涤剂不可溶的部分中。
Core spliceosome and related RNA-binding proteins aggregate in Alzheimer’s disease (AD) brain even in early asymptomatic stages (AsymAD) of disease. To assess the specificity of RNA-binding protein aggregation in AD, we developed a targeted mass spectrometry approach to quantify broad classes of RNA-binding proteins with other pathological proteins including tau and amyloid beta (Aβ) in detergent insoluble fractions from control, AsymAD, AD and Parkinson’s disease (PD) brain. Relative levels of specific insoluble RNA-binding proteins across different disease groups correlated with accumulation of Aβ and tau aggregates. RNA-binding proteins, including splicing factors with homology to the basic-acidic dipeptide repeats of U1-70K, preferentially aggregated in AsymAD and AD. In contrast, PD brain aggregates were relatively depleted of many RNA-binding proteins compared to AsymAD and AD groups. Correlation network analyses resolved 29 distinct modules of co-aggregating proteins including modules linked to spliceosome assembly, nuclear speckles and RNA splicing. Modules related to spliceosome assembly and nuclear speckles showed stage-specific enrichment of insoluble RBPs from AsymAD and AD brains, whereas the RNA splicing module was reduced specifically in PD. Collectively, this work identifies classes of RNA-binding proteins that distinctly co-aggregate in detergent-insoluble fractions across the specific neurodegenerative diseases we examined.
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DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
影响因子：
1.2
作者：
Diner, Ian;Tram Nguyen;Seyfried, Nicholas T.
通讯作者：
Seyfried, Nicholas T.
影响因子：
48
作者：
Gillette, Michael A.;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
19
作者：
Boeynaems S;Alberti S;Fawzi NL;Mittag T;Polymenidou M;Rousseau F;Schymkowitz J;Shorter J;Wolozin B;Van Den Bosch L;Tompa P;Fuxreiter M
通讯作者：
Fuxreiter M
影响因子：
25
作者：
Apicco DJ;Ash PEA;Maziuk B;LeBlang C;Medalla M;Al Abdullatif A;Ferragud A;Botelho E;Ballance HI;Dhawan U;Boudeau S;Cruz AL;Kashy D;Wong A;Goldberg LR;Yazdani N;Zhang C;Ung CY;Tripodis Y;Kanaan NM;Ikezu T;Cottone P;Leszyk J;Li H;Luebke J;Bryant CD;Wolozin B
通讯作者：
Wolozin B