Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease.
Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease.
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DOI：
10.1002/pmic.201500059
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发表时间：
2015-09
期刊：
影响因子：
3.4
通讯作者：
Manuelidis L
中科院分区：
文献类型：
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作者：
Kipkorir T;Colangelo CM;Manuelidis L
传染性脑病（TSE），如CJD和羊瘙痒症，是由引起菌株特异性疾病模式的传染性病原体引起的。错误折叠的宿主朊蛋白（PrP-res淀粉样蛋白）被认为是致病性感染因子。然而，剥离PrP的颗粒保留了高感染性和在未感染的小鼠对照中检测不到的病毒蛋白。在这里，我们详细的宿主蛋白结合FU-CJD感染性脑颗粒蛋白质组学分析。去除PrP、GFAP、C1 q、ApoE等晚期病理反应蛋白后，共发现56个FU-CJD特异性蛋白。剥离的FU-CJD颗粒揭示了HSC 70（未感染对照的144倍），亲环素B，许多病毒所需的FU-CJD专有蛋白，以及已知促进病毒加工，复制和传播的早期内体-膜途径。突触体元件包括突触蛋白-2（33×）和AP 180（一种主要的FU-CJD排他性蛋白），它们证实了25 nm病毒样TSE颗粒的已知超微结构位置和突触中的感染性。还发现了没有明显病毒或神经退行性联系的蛋白质（copine-3），以及其他参与病毒诱导的蛋白质错误折叠和聚集的蛋白质。人类sCJD脑颗粒含有146种排他性蛋白质，除了阿尔茨海默病（AD）、帕金森病和亨廷顿聚集蛋白外，热休克、突触和病毒途径也很突出。结合TSE感染性颗粒的宿主蛋白质可以阻止宿主免疫识别，并有助于延长跨物种传播（物种屏障）。我们的感染性颗粒策略将背景序列减少了> 99%，强调了新治疗方案的宿主靶点。这种疗法可以同时颠覆神经变性的常见途径。
Transmissible encephalopathies (TSEs), such as CJD and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144× the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33×) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic and viral pathways were again prominent, in addition to Alzheimer (AD), Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration.