Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.
Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.
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朊病毒蛋白聚糖可减少朊病毒疾病中的脑内原纤维形成和海绵组织形成。
DOI：
10.1172/jci131564
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Nilsson,KPeter
中科院分区：
文献类型：
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作者：
Sevillano,AlejandroM;Aguilar-Calvo,Patricia;Kurt,TimothyD;Lawrence,JessicaA;Soldau,Katrin;Nam,ThuH;Schumann,Taylor;Pizzo,DonaldP;Nyström,Sofie;Choudhury,Biswa;Altmeppen,Hermann;Esko,JeffreyD;Glatzel,Markus;Nilsson,KPeter
翻译后修饰(PTM)在聚集在神经退行性疾病中的蛋白质中很常见，然而PTM如何影响聚集构象和疾病进展仍不清楚。通过对缺乏2个N-连接糖链的PrP基因敲打小鼠(Prnp180Q/196Q)进行工程改造，我们提供了多聚糖可减少海绵状变性并阻止PrP疾病斑块形成的证据。Prnp180Q/196Q小鼠被2个亚纤维、非空斑形成的PrP菌株攻击后，出现了高度富含ADAM10裂解PrP和硫酸乙酰肝素(HS)的斑块。有趣的是，第三个菌株由完整的糖磷脂酰肌醇锚定(GPI锚定)PrP组成，相对没有变化，在Prnp180Q/196Q和WT小鼠中都形成了弥漫的HS缺陷沉积，强调了GPI锚定在驱动聚集体构象和疾病表型方面的关键作用。最后，表达三糖基化PrP(Prnp187N)的敲击小鼠用形成空斑的普恩病毒株攻击后表现出表型逆转，疾病加速，并从空斑转变为以弥漫为主的亚纤维沉积。我们的发现表明，在Pron病中，亚纤维聚集的优势是由于GPI锚定的Prion的复制，纤维斑块形成于与细胞外HS相互作用的糖基化程度较低的GPI锚定的Prion。这些研究提供了对PTMS如何影响PrP与多阴离子辅助因子相互作用的洞察，并强调PTMS是驱动Prion疾病表型的主要力量。
Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion disease.Prnp180Q/196Qmice challenged with 2 subfibrillar, non–plaque-forming prion strains instead developed plaques highly enriched in ADAM10-cleaved PrP and heparan sulfate (HS). Intriguingly, a third strain composed of intact, glycophosphatidylinositol-anchored (GPI-anchored) PrP was relatively unchanged, forming diffuse, HS-deficient deposits in both thePrnp180Q/196Qand WT mice, underscoring the pivotal role of the GPI-anchor in driving the aggregate conformation and disease phenotype. Finally, knockin mice expressing triglycosylated PrP (Prnp187N) challenged with a plaque-forming prion strain showed a phenotype reversal, with a striking disease acceleration and switch from plaques to predominantly diffuse, subfibrillar deposits. Our findings suggest that the dominance of subfibrillar aggregates in prion disease is due to the replication of GPI-anchored prions, with fibrillar plaques forming from poorly glycosylated, GPI-anchorless prions that interact with extracellular HS. These studies provide insight into how PTMs impact PrP interactions with polyanionic cofactors, and highlight PTMs as a major force driving the prion disease phenotype.