Fundamental study on the molecular mechanism for neuropathological changes of dementia

痴呆神经病理改变分子机制的基础研究

基本信息

批准号：
13210119
负责人：
MORI Hiroshi
金额：
$ 35.84万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13210119/
关键词：
Neuroscience Dementia splicing neurodegeneration tau exon 10 tauopachy 脳・神経老化タウ蛋白

项目摘要

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.

神经原纤维缠结是阿尔茨海默氏病淀粉样蛋白斑块旁边的主要大脑病理变化，在各种痴呆症疾病中常见，称为tauopachy，其中包括tau蛋白的相同或相似变化。 tau基因具有独立的能力引起某些痴呆症，例如FTDP-17，表明Tau基因编码主要和因果关系。尽管发现了FTDP-17的大量差异系列，但大多数疾病是由外显子10剪接的异常引起的。我们取出了基因组片段，包括人类感兴趣的外显子10，并广泛地对其进行了特征，并提倡有关新机制，并提倡有关新机制。外显子O剪接。从Hutton和Schellenberg组提出的两个模型中，我们的新模型是根据双茎环结构提出的。在我们的模型中，有人提出，第二个茎循环在内含子10控制的外显子10剪接与常规的第一个茎循环中以负调控方式合作进一步。此外，为了在不仅在培养细胞中而且在脑组织中看到基于该模型的剪接控制，我们制造了转基因小鼠。它证明，在当前DNA构建过程中开发过程中同工型变化的所有决定性信息。基于这个新模型，我们认为包括阿尔茨海默氏病阶段的陶氏症的基本原因不是tau蛋白本身，而是在影响外显子10表达的剪接机制的异常中。

项目成果

期刊论文数量（152）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Impaired cell cycle control of neuronal precursor cells in the neocortical primordium of presenilin-1-deficient mice.

presenilin-1 缺陷小鼠新皮质原基中神经元前体细胞的细胞周期控制受损。

DOI：
发表时间：
2002
期刊：
J Neurosci Res. 70
影响因子：
0
作者：
Yuasa S;Nakajima M;Aizawa H;Sahara N;Koizumi K;Sakai T;Usami M;Kobayashi S;Kuroyanagi H;Mori H;Koseki H;Shirasawa T.
通讯作者：
Shirasawa T.

Altered Metabolism of the Amyloid bPrecursor Protein Is Associated with Mitochondrial Dysfunction in Down's Syndrome.

淀粉样 b 前体蛋白代谢的改变与唐氏综合症的线粒体功能障碍有关。