Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Nash Family Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
CNS Neurosci Ther. 2024 Jun;30(6):e14304. doi: 10.1111/cns.14304. Epub 2023 Jun 21.
The primary histological characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which are large aggregates of tau protein. Aging is the primary risk factor for the development of Alzheimer's disease, however, the underlying causes of tau protein aggregation and toxicity are unclear.
Here we investigated tau aggregation and toxicity under the conditions of compromised protein homeostasis.
We used heterologous expression of human tau protein in the unicellular eukaryote yeast Saccharomyces cerevisiae with evolutionarily conserved protein quality control pathways and examined tau-dependent toxicity and aggregation using growth assays, fluorescence microscopy, and a split luciferase-based reporter NanoBiT.
Tau protein expressed in yeast under mild proteotoxic stress, or in mutants with impaired pathways for proteotoxic stress response, did not lead to synthetic toxicity or the formation of obvious aggregates. Chronologically old cells also did not develop observable tau aggregates. Our examination of tau oligomerization in living cells using NanoBiT reporter suggests that tau does not form significant levels of oligomers under basal conditions or under mild proteotoxic stress.
Together our data suggest that human tau protein does not represent a major burden to the protein quality control system in yeast cells.
阿尔茨海默病的主要组织学特征是存在神经原纤维缠结，这是tau 蛋白的大聚集体。衰老是阿尔茨海默病发展的主要危险因素，然而，tau 蛋白聚集和毒性的潜在原因尚不清楚。
本研究旨在探讨在蛋白质平衡受损的情况下 tau 聚集和毒性的情况。
我们使用真核单细胞酵母酿酒酵母中异源表达人类 tau 蛋白，利用进化保守的蛋白质质量控制途径，并使用生长测定、荧光显微镜和基于分裂萤光素酶的 NanoBiT 报告子来检测 tau 依赖性毒性和聚集。
在轻度蛋白毒性应激下或在蛋白毒性应激反应途径受损的突变体中表达的 tau 蛋白不会导致合成毒性或明显聚集的形成。衰老的酵母细胞也没有形成可观察到的 tau 聚集物。我们使用 NanoBiT 报告子在活细胞中检查 tau 寡聚化的情况表明，tau 在基础条件或轻度蛋白毒性应激下不会形成显著水平的寡聚体。
总的来说，我们的数据表明人类 tau 蛋白对酵母细胞的蛋白质质量控制系统不会构成重大负担。
