Department of Molecular Biosciences , University of Kansas , 1200 Sunnyside Ave , Lawrence , Kansas 66045 , United States.
Department of Translational Science & Molecular Medicine, College of Human Medicine , Michigan State University , Grand Rapids , Michigan 49503 , United States.
Biochemistry. 2019 Feb 12;58(6):742-754. doi: 10.1021/acs.biochem.8b01039. Epub 2018 Dec 31.
More than 50 different intronic and exonic autosomal dominant mutations in the tau gene have been linked to the neurodegenerative disorder frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17). Although the pathological and clinical presentation of this disorder is heterogeneous among patients, the deposition of tau as pathological aggregates is a common feature. Collectively, FTDP-17 mutations have been shown to alter tau's ability to stabilize microtubules, enhance its aggregation, alter mRNA splicing, or induce its hyperphosphorylation, among other effects. Previous in vitro studies from our lab revealed that these mutations differ markedly from each other in the longest 2N4R isoform of tau. However, it is not entirely known whether the effect of a single mutation varies when compared between different isoforms of tau. Differences in the isoelectric points of the N-terminal region of tau isoforms lead to changes in their biochemical properties, raising the possibility that isoforms could also be disproportionately affected by disease-related mechanisms such as mutations. We therefore performed a comparative study of three FTDP-17 mutations present in different regions of tau (R5L, P301L, and R406W) in the three 4R isoforms of tau. We observed significant differences in the effect these mutations exert on the total amount and kinetics of aggregation, aggregate length distributions, and microtubule stabilizing propensity of 4R tau isoforms for all three selected mutants. These results demonstrate that different combinations of FTDP-17 mutations and tau isoforms are functionally distinct and could have important implications for our understanding of disease and animal models of tauopathies.
已经有超过 50 种不同的位于 tau 基因上的常染色体显性突变与神经退行性疾病额颞叶痴呆伴帕金森病相关（FTDP-17）相关联。尽管这种疾病在患者之间的病理和临床表现存在异质性，但 tau 作为病理性聚集体的沉积是一个共同特征。总的来说，FTDP-17 突变已被证明会改变 tau 稳定微管的能力、增强其聚集、改变 mRNA 剪接或诱导其过度磷酸化等。我们实验室之前的体外研究表明，这些突变在 tau 的最长 2N4R 异构体中彼此之间有明显的差异。然而，当比较 tau 的不同异构体时，单个突变的影响是否不同，目前还不完全清楚。tau 异构体 N 端区域等电点的差异导致其生化特性发生变化，这增加了这样一种可能性，即异构体也可能受到与疾病相关的机制（如突变）的不成比例的影响。因此，我们在 tau 的三个不同区域（R5L、P301L 和 R406W）中进行了三种 FTDP-17 突变在三种 4R 异构体 tau 中的比较研究。我们观察到这些突变对 4R tau 异构体的总聚集量和动力学、聚集长度分布以及微管稳定倾向的影响存在显著差异，所有三个选定的突变体都是如此。这些结果表明，不同的 FTDP-17 突变和 tau 异构体的组合在功能上是不同的，这可能对我们理解疾病和 tau 病的动物模型具有重要意义。
