Fundamental study on the molecular mechanism for neuropathological changes of dementia

神经元缠结是阿尔茨海默病中淀粉样蛋白斑块之外的主要脑病理变化，并且在包括tau蛋白的相同或相似变化的被称为tau蛋白质病的各种痴呆疾病中常见。TAU基因能够独立地引起FTDP-17等痴呆，表明TAU基因是主要的致病基因。虽然发现了FTDP- 17的许多变异家族，但大多数疾病是由外显子10的剪接异常引起的。我们从人类基因组中提取了包括外显子10在内的基因组片段，对外显子O剪接的新机制进行了广泛的表征和倡导，在赫顿和谢伦贝格两组模型的基础上，提出了基于双茎环结构的新模型。在我们的模型中，第二茎环进一步在内含子10下游控制外显子10剪接与传统的第一茎环以负调控方式合作。此外，为了不仅在培养细胞中而且在脑组织中观察基于该模型的剪接控制，我们制造了转基因小鼠。这证明了在本DNA构建体中，同种型的所有决定性信息在发育过程中发生了变化。基于这种新模型，我们认为，包括阿尔茨海默病阶段在内的tau蛋白质不稳定的根本原因不在于tau蛋白本身，而在于影响外显子10表达的剪接机制的异常。

Neurofibrillary tangles are the main brain pathological changes beside amyloid plaques in Alzheimer's disease and common in various dementia diseases referred to as tauopachy that include the same or similar changes of tau proteins. TAU gene is independently capable to cause some dementia such as FTDP-17, indicating that TAU gene encodes the major and causative. Although much variation family lines of FTDP- 17 are discovered, the majority of the disease was caused by the abnormalities in splicing of exon 10. We took out the genome fragment including exon 10 in interest from humans and extensively characterized and advocated the new mechanism about exon O splicing.Differently from two models proposed by Hutton and Schellenberg groups, our new model was proposed based on the double stem loop structure. In our model, it was suggested that the 2nd stem loop further in a down stream of intron 10 controlled exon 10 splicing cooperatively with the conventional first stem loop in a negatively regulation manner. Moreover, in order to see the splicing control based on this model in not only culture cells but also brain tissue, we made the transgenic mice. It proved that all the decisive information for an isoform change during development in the present DNA construct. Based on this new model, we think that the essential cause of tauopachy including a phase of Alzheimer's disease is not in tau protein itself, but in the abnormalities of a splicing mechanism that influences an expression of exon 10.