Deciphering the cellular mechanism of seeded prion aggregation in neuronal cells

Prion病是一种脑传染病，对动物和人类都有影响，包括绵羊的瘙痒病、牛的牛海绵状脑病(BSE)和人类的克雅氏病(CJD)。尽管最近几十年来，作为Pron病的感染性病原体，Prion已经得到了彻底的表征，但我们仍然没有发现它们在神经细胞中繁殖的细胞机制。虽然Prion被认为是通过将表达在神经元表面的细胞Prion蛋白(PrPc)转换为与疾病相关的自身构象来进行复制的，但细胞位置和复制的分子机制仍然是个谜。我们的初步数据为疾病相关PrP(PrPD)如何在神经元细胞质膜上形成新的聚集体提供了第一个分子线索。PRPD变异检测的突破性进展使我们能够区分细胞内和细胞外的PRPD聚集体。这有助于我们推断，纤维状PRPD聚集体在质膜上的组装和生长是由细胞内的聚集种子驱动的。重要的是，抑制和刺激这些种子到质膜的运输分别阻止和促进了纤维生长。我们计划与弗朗西斯·克里克研究所的蛋白质分泌专家Sharon Tooze教授一起，研究PRPD细胞内池如何到达质膜的分子机制。这一点非常重要，因为我们的初步数据表明，抑制PRPD向质膜的运输可能会阻止Prion的产生。

Prion diseases, transmissible diseases of the brain, affect animals and humans alike and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. Although prions, the infectious pathogens of prion diseases have been thoroughly characterised over recent decades, we still have not found the cellular mechanism by which they propagate in neuronal cells. While prions are thought to replicate by conversion of the cellular prion protein (PrPc), a protein expressed on the surface of neurons, to disease-associated conformers of itself, the cellular site and the molecular mechanism of replication remain enigmatic.Our preliminary data present the first molecular clues on how new aggregates of disease-associated PrP (PrPd) arise at the plasma membrane of neuronal cells. A breakthrough in the detection of PrPd variants enabled us to distinguish intracellular from extracellular PrPd aggregates. This helped us to infer that the assembly and growth of fibrillar PrPd aggregates at the plasma membrane is driven by aggregation seeds from inside the cell. Importantly, inhibition and stimulation of the transport of these seeds to the plasma membrane prevented and accelerated fibril growth, respectively.Together with Prof Sharon Tooze, an expert in protein secretion from the Francis Crick Institute, we plan to investigate the molecular mechanism on how the intracellular pool of PrPd reaches the plasma membrane. This is of great importance, since our preliminary data suggest inhibiting the transport of PrPd on its way to the plasma membrane may block the generation of prions.