Zhou Jianhua, Yu Qingming, Zou Tie
Department of Medicine, Program in Neuroscience, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
BMC Neurosci. 2008 Dec 3;9 Suppl 2(Suppl 2):S10. doi: 10.1186/1471-2202-9-S2-S10.
Tau aggregation is one of the major features in Alzheimer's disease and in several other tauopathies, including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), and progressive supranuclear palsy (PSP). More than 35 mutations in the tau gene have been identified from FTDP-17 patients. A group of these mutations alters splicing of exon 10, resulting in an increase in exon 10 inclusion into tau mRNA. Abnormal splicing with inclusion of exon 10 into tau mRNA has also been observed in PSP and AD patients. These results indicate that abnormal splicing of exon 10, leading to the production of tau with exon 10, is probably one of the mechanisms by which tau accumulates and aggregates in tauopathic brains. Therefore, modulation of exon 10 splicing in the tau gene could potentially be targeted to prevent tauopathies. To identify small molecules or compounds that could potentially be developed into drugs to treat tauopathies, we established a cell-based high-throughput screening assay. In this review, we will discuss how realistic, specific biological molecules can be found to regulate exon 10 splicing in the tau gene for potential treatment of tauopathies.
tau蛋白聚集是阿尔茨海默病以及其他几种tau蛋白病的主要特征之一，这些疾病包括与17号染色体相关的额颞叶痴呆伴帕金森综合征（FTDP-17）和进行性核上性麻痹（PSP）。已从FTDP-17患者中鉴定出超过35种tau基因的突变。其中一组突变改变了外显子10的剪接，导致外显子10包含在tau mRNA中的比例增加。在PSP和AD患者中也观察到外显子10异常剪接并包含在tau mRNA中。这些结果表明，外显子10的异常剪接导致含外显子10的tau蛋白产生，这可能是tau蛋白在tau蛋白病大脑中积累和聚集的机制之一。因此，调节tau基因中外显子10的剪接可能是预防tau蛋白病的潜在靶点。为了鉴定可能开发成治疗tau蛋白病药物的小分子或化合物，我们建立了基于细胞的高通量筛选试验。在这篇综述中，我们将讨论如何找到切实可行的特定生物分子来调节tau基因中外显子10的剪接，以潜在治疗tau蛋白病。
