Elucidating the mechanism of prion replication promiscuity

阐明朊病毒复制混乱的机制

• 批准号: RGPIN-2015-05112
• 负责人: Watts, Joel
• 金额: $ 3.13万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688622
• 关键词: Elucidating; mechanism; prion; replication; promiscuity

The presence of misfolded, aggregated proteins in the brain is a hallmark of many human neurodegenerative diseases. Of particular interest are the prion diseases, which include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE, or "mad cow disease") in cattle. In these diseases, misshapen proteins called prions accumulate in the brain, eventually resulting in the death of brain cells. Prions are notorious for being infectious proteins. Generally, prions from one species do not efficiently infect other species, a process referred to as the "species barrier". Sometimes, the species barrier is imperfect, as in the case of the transmission of BSE prions to humans during the mad cow disease epidemic in the United Kingdom. Some animal species, such as rabbits and dogs, are seemingly resistant to prion disease. At the other end of the spectrum, bank voles (Myodes glareolus) are susceptible to prions from many different species, suggesting that they do not impose a species barrier for prions. Thus, bank voles provide a unique opportunity to study the transfer of prions from one species to another. My previous work has demonstrated that bank voles produce a prion protein that is extremely susceptible to misfolding both spontaneously and upon exposure to prions from other species. The objectives of this Discovery Grant are to determine why the bank vole prion protein is "promiscuous" for replicating prions and why it is much more prone to misfolding than prion proteins from other species. To accomplish these goals, we will utilize a multi-faceted approach involving purified proteins, cultured cells, and genetically engineered mice in conjunction with powerful biochemical tools for studying protein misfolding. This research will provide insight into the molecular details of prion misfolding and interspecies prion transmission. More generally, this work has important implications for understanding why proteins misfold, preventing future outbreaks of prion disease, and for developing strategies to prevent or reverse protein aggregation in the brain.

大脑中存在错误折叠、聚集的蛋白质是许多人类神经退行性疾病的标志。特别令人感兴趣的是朊病毒疾病，包括人类的克雅氏病（CJD）和牛的牛海绵状脑病（BSE，或“疯牛病”）。在这些疾病中，被称为朊病毒的畸形蛋白质在大脑中积聚，最终导致脑细胞死亡。朊病毒是臭名昭著的传染性蛋白质。一般来说，一个物种的朊病毒不能有效地感染其他物种，这一过程被称为“物种屏障”。有时，物种屏障是不完善的，就像在英国疯牛病流行期间疯牛病朊病毒向人类传播的情况一样。一些动物物种，如兔子和狗，似乎对朊病毒疾病有抵抗力。在光谱的另一端，银行田鼠（Myodes glareolus）对来自许多不同物种的朊病毒敏感，这表明它们不会对朊病毒施加物种屏障。因此，银行田鼠提供了一个独特的机会来研究朊病毒从一个物种到另一个物种的转移。我之前的工作已经证明，银行田鼠产生一种朊病毒蛋白，这种蛋白非常容易自发地或在接触其他物种的朊病毒时发生错误折叠。这项发现基金的目标是确定为什么银行田鼠朊病毒蛋白在复制朊病毒时是“混杂的”，以及为什么它比其他物种的朊病毒蛋白更容易发生错误折叠。为了实现这些目标，我们将利用多方面的方法，包括纯化蛋白质、培养细胞和基因工程小鼠，并结合强大的生化工具来研究蛋白质错误折叠。这项研究将为朊病毒错误折叠和种间传播的分子细节提供见解。更广泛地说，这项工作对于理解蛋白质错误折叠的原因、预防未来朊病毒疾病的爆发以及制定防止或逆转大脑中蛋白质聚集的策略具有重要意义。