Cofactors are essential for driving recombinant prion protein into pathogenic conformers. Polyanions promote prion aggregation in vitro, yet the cofactors that modulate prion assembly in vivo remain largely unknown. Here we report that the endogenous glycosaminoglycan, heparan sulfate (HS), impacts prion propagation kinetics and deposition sites in the brain. Exostosin-1 haploinsufficient (Ext1^+/−) mice, which produce short HS chains, show a prolonged survival and a redistribution of plaques from the parenchyma to vessels when infected with fibrillar prions, and a modest delay when infected with subfibrillar prions. Notably, the fibrillar, plaque-forming prions are composed of ADAM10-cleaved prion protein lacking a glycosylphosphatidylinositol anchor, indicating that these prions are mobile and assemble extracellularly. By analyzing the prion-bound HS using liquid chromatography–mass spectrometry (LC–MS), we identified the disaccharide signature of HS differentially bound to fibrillar compared to subfibrillar prions, and found approximately 20-fold more HS bound to the fibrils. Finally, LC–MS of prion-bound HS from human patients with familial and sporadic prion disease also showed distinct HS signatures and higher HS levels associated with fibrillar prions. This study provides the first in vivo evidence of an endogenous cofactor that accelerates prion disease progression and enhances parenchymal deposition of ADAM10-cleaved, mobile prions.

中文翻译：

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缩短硫酸乙酰肝素链可延长存活期并减少由移动的、ADAM10 切割的朊病毒引起的朊病毒病中的实质斑块。

辅因子对于将重组朊病毒蛋白驱动为致病构象异构体至关重要。聚阴离子在体外促进朊病毒聚集，但在体内调节朊病毒组装的辅助因子仍然很大程度上未知。在这里，我们报告内源性糖胺聚糖、硫酸乙酰肝素 (HS) 会影响朊病毒传播动力学和大脑中的沉积位点。Exostosin-1 单倍体不足 ( Ext1 ^{+ / -}) 产生短 HS 链的小鼠在感染纤维状朊病毒时表现出延长的存活期和斑块从实质到血管的重新分布，并且在感染亚纤维状朊病毒时表现出适度的延迟。值得注意的是，纤维状、斑块形成朊病毒由 ADAM10 切割的朊病毒蛋白组成，缺乏糖基磷脂酰肌醇锚，表明这些朊病毒是可移动的并在细胞外组装。通过使用液相色谱-质谱 (LC-MS) 分析与朊病毒结合的 HS，我们确定了与亚纤丝朊病毒相比，HS 的二糖特征与原纤维不同地结合，并发现与原纤维结合的 HS 约多 20 倍。最后，来自患有家族性和散发性朊病毒病的人类患者的朊病毒结合 HS 的 LC-MS 也显示出明显的 HS 特征和与纤维状朊病毒相关的更高的 HS 水平。这项研究提供了第一个体内证据，证明内源性辅因子可加速朊病毒疾病的进展并增强 ADAM10 切割的可移动朊病毒的实质沉积。