Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Hněvotínská 1333/5, 77900, Olomouc, Czech Republic.
Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacký University in Olomouc, Olomouc, Czech Republic.
Biochem Biophys Res Commun. 2023 Apr 23;653:102-105. doi: 10.1016/j.bbrc.2023.02.057. Epub 2023 Feb 23.
Tauopathies are a group of neurodegenerative diseases categorised into three types, 3R, 4R, or 3R+4R (mixed) tauopathies, based on the tau isoforms that make up the aberrant filaments. It is supposed that all six tau isoforms share functional characteristics. However, differences in the neuropathological features associated with different tauopathies offer the possibility that disease progression and tau accumulation may vary depending on the isoform composition. The presence or absence of repeat 2 (R2) in the microtubule-binding domain defines the type of isoform, which might influence tau pathology associated with a particular tau isoform. Therefore, our study aimed to identify the differences in the seeding propensities of R2 and repeat 3 (R3) aggregates using HEK293T biosensor cells. We show that the seeding induced by R2 was generally higher than by R3 aggregates, and lower concentrations of R2 aggregates are sufficient to induce seeding. Next, we found that both R2 and R3 aggregates dose-dependently increased triton-insoluble Ser262 phosphorylation of native tau, which is only visible in cells seeded with higher concentrations (12.5 nM or 100 nM) of R2 and R3 aggregates, despite the seeding by the lower concentrations of R2 aggregates after 72 h. However, the accumulation of triton-insoluble pSer262 tau was visible earlier in cells induced with R2 than in R3 aggregates. Our findings suggest that the R2 region may contribute to the early and enhanced induction of tau aggregation and define the difference in disease progression and neuropathology of 4R tauopathies.
tau 病是一组神经退行性疾病，根据构成异常纤维的 tau 异构体，分为 3R、4R 或 3R+4R（混合）tau 病。据推测，所有六种 tau 异构体都具有功能特征。然而，不同 tau 病的神经病理学特征的差异表明，疾病进展和 tau 积累可能因异构体组成而异。微管结合域中重复 2（R2）的存在或缺失定义了异构体的类型，这可能影响与特定 tau 异构体相关的 tau 病理学。因此，我们的研究旨在使用 HEK293T 生物传感器细胞鉴定 R2 和重复 3（R3）聚集体的成核倾向差异。我们表明，R2 诱导的成核通常高于 R3 聚集体，并且较低浓度的 R2 聚集体足以诱导成核。接下来，我们发现 R2 和 R3 聚集体均剂量依赖性地增加了天然 tau 的 Triton 不溶性 Ser262 磷酸化，尽管在 72 小时后用较低浓度的 R2 聚集体进行成核后，仅在细胞中可见浓度较高（12.5 nM 或 100 nM）的 R2 和 R3 聚集体。然而，R2 聚集体诱导的细胞中 triton 不溶性 pSer262 tau 的积累更早出现。我们的研究结果表明，R2 区域可能有助于 tau 聚集的早期和增强诱导，并定义 4R tau 病的疾病进展和神经病理学差异。
