Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado, USA.
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado, USA.
J Biol Chem. 2021 Sep;297(3):101021. doi: 10.1016/j.jbc.2021.101021. Epub 2021 Jul 31.
Oxidative stress has been implicated in the pathogenesis and progression of several tauopathies, including Alzheimer's disease. The deposition of fibrillar inclusions made of tau protein is one of the pathological hallmarks of these disorders. Although it is becoming increasingly evident that the specific fibril structure may vary from one tauopathy to another and it is recognized that different types of isoforms (three-repeat and four-repeat tau) can be selectively deposited, little is known about the role oxidation may play in aggregation. Four-repeat tau contains two cysteines that can form an intramolecular disulfide bond, resulting in a structurally restrained compact monomer. There is discrepancy as to whether this monomer can aggregate or not. Using isolated four-repeat tau monomers (htau40) with intramolecular disulfide bonds, we demonstrate that these proteins form fibrils. The fibrils are less stable than fibrils formed under reducing conditions but are highly effective in seeding oxidized tau monomers. Conversely, a strong seeding barrier prevents incorporation of reduced tau monomers, tau mimics in which the cysteines have been replaced by alanines or serines, and three-repeat tau (htau23), a single-cysteine isoform. The barrier also holds true when seed and monomer types are reversed, indicating that oxidized and reduced tau are incompatible with each other. Surprisingly, fibrils composed of compact tau disaggregate upon reduction, highlighting the importance of the intramolecular disulfide bond for fibril stability. The findings uncover a novel binary redox switch that controls the aggregation and disaggregation of these fibrils and extend the conformational spectrum of tau aggregates.
氧化应激与几种 tau 病的发病机制和进展有关，包括阿尔茨海默病。tau 蛋白纤维状包涵体的沉积是这些疾病的病理标志之一。尽管越来越明显的是，特定的纤维结构可能因一种 tau 病而异，并且已经认识到不同类型的异构体（三重复和四重复 tau）可以选择性沉积，但关于氧化可能在聚集中起作用的了解甚少。四重复 tau 包含两个半胱氨酸，可以形成一个分子内二硫键，导致结构受限的紧凑单体。关于这种单体是否可以聚集存在争议。使用具有分子内二硫键的分离的四重复 tau 单体（htau40），我们证明这些蛋白质可以形成纤维。与在还原条件下形成的纤维相比，这些纤维的稳定性较差，但在氧化 tau 单体的种子中非常有效。相反，强烈的种子障碍阻止还原 tau 单体、半胱氨酸被替换为丙氨酸或丝氨酸的 tau 模拟物以及单半胱氨酸异构体三重复 tau（htau23）的掺入。当种子和单体类型反转时，该障碍仍然有效，这表明氧化和还原 tau 彼此不相容。令人惊讶的是，由紧凑 tau 组成的纤维在还原时解聚，突出了分子内二硫键对纤维稳定性的重要性。这些发现揭示了一种新的二元氧化还原开关，该开关控制这些纤维的聚集和解聚，并扩展了 tau 聚集的构象谱。
