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Deciphering the cellular mechanism of seeded prion aggregation in neuronal cells

破译种子朊病毒在神经元细胞中聚集的细胞机制

基本信息

批准号：
BB/V001310/1
负责人：
Peter Kloehn
金额：
$ 52.67万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV001310%2F1
关键词：
Deciphering cellular mechanism seeded prion

项目摘要

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.

朊病毒疾病是脑部的传染性疾病，对动物和人类都有影响，包括绵羊的瘙痒病、牛的牛海绵状脑病和人类的克雅氏病。虽然朊病毒，朊病毒疾病的传染性病原体已彻底的特点，在最近几十年来，我们仍然没有发现的细胞机制，它们在神经细胞中传播。虽然朊病毒被认为是复制的细胞朊病毒蛋白（PrPc），在神经元的表面上表达的蛋白质，疾病相关的构象本身的转换，细胞的网站和复制的分子机制仍然是谜。我们的初步数据提出了第一个分子线索，疾病相关的PrP（PrPd）的新聚集体出现在神经元细胞的质膜。在检测PrPd变体方面的突破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的运输到质膜阻止和加速原纤维的生长，分别与教授Sharon Tooze，在蛋白质分泌专家从弗朗西斯克里克研究所，我们计划调查的分子机制上的细胞内池的PrPd如何到达质膜。这是非常重要的，因为我们的初步数据表明，抑制PrPd转运到质膜可能会阻止朊病毒的产生。