Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
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DOI：
10.1371/journal.pone.0113070
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Höglinger G
中科院分区：
文献类型：
--
作者：
Bruch J;Xu H;De Andrade A;Höglinger G
进行性核上性麻痹（PSP）是一种以细胞内微管相关蛋白tau聚集为特征的神经退行性疾病。tau蛋白存在于6种主要亚型中。根据外显子10的选择性剪接，这些同工异构体中有三个具有四个微管结合重复结构域（4R），而其他异构体只有三个（3R）。在PSP中有过量的4R tau亚型，这被认为对病理过程有重要贡献。这种4R增加的原因至今尚不清楚。一些证据表明线粒体复合体I的抑制与PSP的发病机制有关。我们在这里首次证明，两种典型的线粒体复合体I抑制剂，annonacin和MPP+，增加了人类神经元中tau蛋白的4R亚型。我们发现剪接因子SRSF2是增加4R tau复合物I抑制所必需的。我们还发现SRSF2以及另一种tau剪接因子TRA2B在PSP患者的大脑中增加。因此，我们提供了新的证据，证明线粒体复合体I抑制可能是PSP发病的上游事件，并表明剪接因子可能是干预疾病过程的一个有吸引力的治疗靶点。
Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by intracellular aggregation of the microtubule-associated protein tau. The tau protein exists in 6 predominant isoforms. Depending on alternative splicing of exon 10, three of these isoforms have four microtubule-binding repeat domains (4R), whilst the others only have three (3R). In PSP there is an excess of the 4R tau isoforms, which are thought to contribute significantly to the pathological process. The cause of this 4R increase is so far unknown. Several lines of evidence link mitochondrial complex I inhibition to the pathogenesis of PSP. We demonstrate here for the first time that annonacin and MPP+, two prototypical mitochondrial complex I inhibitors, increase the 4R isoforms of tau in human neurons. We show that the splicing factor SRSF2 is necessary to increase 4R tau with complex I inhibition. We also found SRSF2, as well as another tau splicing factor, TRA2B, to be increased in brains of PSP patients. Thereby, we provide new evidence that mitochondrial complex I inhibition may contribute as an upstream event to the pathogenesis of PSP and suggest that splicing factors may represent an attractive therapeutic target to intervene in the disease process.
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影响因子：
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