Department of Pharmacology, Ajou University School of Medicine, Suwon 442-749, Korea.
J Neurochem. 2010 Jul;114(1):160-70. doi: 10.1111/j.1471-4159.2010.06732.x. Epub 2010 Apr 3.
Alternative splicing of tau exon 10 influences microtubule assembly and stability during development and in pathological processes of the central nervous system. However, the cellular events that underlie this pre-mRNA splicing remain to be delineated. In this study, we examined the possibility that ischemic injury, known to change the cellular distribution and expression of several RNA splicing factors, alters the splicing of tau exon 10. Transient occlusion of the middle cerebral artery reduced tau exon 10 inclusion in the ischemic cortical area within 12 h, resulting in the induction of three-repeat (3R) tau in cortical neurons. Ubiquitinated protein aggregates and reduced proteasome activity were also observed. Administration of proteasome inhibitors such as MG132, proteasome inhibitor I and lactacystin reduced tau exon 10 splicing in cortical cell cultures. Decreased levels of Tra2beta, an RNA splicing factor responsible for tau exon 10 inclusion, were detected both in cortical cell cultures exposed to MG132 and in cerebral cortex after ischemic injury. Taken together, these findings suggest that transient focal cerebral ischemia reduces tau exon 10 splicing through a mechanism involving proteasome-ubiquitin dysfunction and down-regulation of Tra2beta.
外显子 10 的 tau 可变剪接影响发育过程中和中枢神经系统病理过程中的微管组装和稳定性。然而，这种前体 mRNA 剪接所依赖的细胞事件仍有待阐明。在这项研究中，我们研究了这样一种可能性，即已知改变几种 RNA 剪接因子的细胞分布和表达的缺血性损伤是否改变 tau 外显子 10 的剪接。大脑中动脉短暂闭塞导致缺血性皮质区域内 tau 外显子 10 的内含子减少，导致皮质神经元中 3 重复（3R）tau 的诱导。还观察到泛素化蛋白聚集体和蛋白酶体活性降低。在皮质细胞培养物中给予蛋白酶体抑制剂，如 MG132、蛋白酶体抑制剂 I 和乳清酸钙，可减少 tau 外显子 10 的剪接。在暴露于 MG132 的皮质细胞培养物和缺血性损伤后的大脑皮质中，检测到负责 tau 外显子 10 内含子的 RNA 剪接因子 Tra2beta 的水平降低。综上所述，这些发现表明，短暂的局灶性脑缺血通过涉及蛋白酶体-泛素功能障碍和 Tra2beta 下调的机制减少 tau 外显子 10 的剪接。
