Elucidating the mechanism of prion replication promiscuity

脑中错误折叠、聚集的蛋白质的存在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，其中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，称为朊病毒的畸形蛋白质在大脑中积累，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，来自一个物种的朊病毒不会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，例如在英国疯牛病流行期间BSE朊病毒向人类传播的情况。一些动物物种，如兔子和狗，似乎对朊病毒病有抵抗力。另一方面，河岸田鼠（Myodes glareolus）对来自许多不同物种的朊病毒敏感，这表明它们对朊病毒没有物种障碍。因此，银行田鼠提供了一个独特的机会，研究朊病毒从一个物种转移到另一个物种。我以前的工作已经证明，银行田鼠产生的朊病毒蛋白，是非常容易错误折叠自发和暴露于朊病毒从其他物种。这项发现补助金的目的是确定为什么银行田鼠朊病毒蛋白是“混杂”复制朊病毒，为什么它更容易错误折叠比其他物种的朊病毒蛋白。为了实现这些目标，我们将利用多方面的方法，包括纯化的蛋白质，培养的细胞和基因工程小鼠，以及强大的生物化学工具来研究蛋白质错误折叠。这项研究将提供深入了解朊病毒错误折叠和种间朊病毒传播的分子细节。更一般地说，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预防或逆转大脑中蛋白质聚集的策略具有重要意义。

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.