Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Research Center for Environment and Health, Zhongnan University of Economics and Law, Wuhan 430073, China.
Cell Rep. 2023 Nov 28;42(11):113342. doi: 10.1016/j.celrep.2023.113342. Epub 2023 Oct 31.
The molecular mechanisms that trigger Tau aggregation in Alzheimer's disease (AD) remain elusive. Fungi, especially Saccharomyces cerevisiae (S. cerevisiae), can be found in brain samples from patients with AD. Here, we show that the yeast protein Ure2p from S. cerevisiae interacts with Tau and facilitates its aggregation. The Ure2p-seeded Tau fibrils are more potent in seeding Tau and causing neurotoxicity in vitro. When injected into the hippocampus of Tau P301S transgenic mice, the Ure2p-seeded Tau fibrils show enhanced seeding activity compared with pure Tau fibrils. Strikingly, intracranial injection of Ure2p fibrils promotes the aggregation of Tau and cognitive impairment in Tau P301S mice. Furthermore, intranasal infection of S. cerevisiae in the nasal cavity of Tau P301S mice accelerates the aggregation of Tau. Together, these observations indicate that the yeast protein Ure2p initiates Tau pathology. Our results provide a conceptual advance that non-mammalian prions may cross-seed mammalian prion-like proteins.
导致阿尔茨海默病（AD）中 Tau 聚集的分子机制仍不清楚。真菌，特别是酿酒酵母（Saccharomyces cerevisiae，S. cerevisiae），可以在 AD 患者的脑组织样本中发现。在这里，我们表明来自 S. cerevisiae 的酵母蛋白 Ure2p 与 Tau 相互作用并促进其聚集。Ure2p 引发的 Tau 纤维在引发 Tau 聚集和体外神经毒性方面更有效。当将 Ure2p 引发的 Tau 纤维注入 Tau P301S 转基因小鼠的海马体中时，与纯 Tau 纤维相比，其具有增强的引发活性。引人注目的是，Ure2p 纤维的颅内注射促进了 Tau 的聚集和 Tau P301S 小鼠的认知障碍。此外，Tau P301S 小鼠鼻腔内的 S. cerevisiae 鼻内感染加速了 Tau 的聚集。总之，这些观察结果表明酵母蛋白 Ure2p 引发了 Tau 病理学。我们的结果提供了一个概念上的进展，即非哺乳动物朊病毒可能跨种子哺乳动物朊病毒样蛋白。
