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Identification of novel genes closely related to Alzheimer's disease

鉴定与阿尔茨海默病密切相关的新基因

基本信息

批准号：
14580722
负责人：
OYAMA Fumitaka
金额：
$ 1.92万
依托单位：
RIKEN (The Institute of Physical and Chemical Research)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14580722/
关键词：
Alzheimer's disease tau tau deficient mouse transcriptome Gem GTPase cell elongation activity

项目摘要

Tau, one of the major microtubule-associated proteins, is involved in neuronal cell morphogenesis and axonal maintenance. Tau is also the major component of paired helical filaments found in the brain affected by Alzheimer's disease. To explore an as yet unidentified role of tau in vivo, 〜11,000 mRNAs were profiled from tau-deficient mouse brains, and compared with those from control brains at the same age. The expression of Gem GTPase, a small GTP binding protein of the ras superfamily, was significantly increased in the brain of tau-deficient mice at eight weeks of age. Because Gem GTPase is a negative regulator of the Rho-Rho kinase pathway for cytoskeletal regulation, this protein was transiently overexpressed in CHO cells that do not express tau. Overexpression of Gem GTPase induced a marked elongation of CHO cells, and simultaneous expression of tau eliminated this effect, although tau is not bound directly to Gem GTPase. This anti-elongation activity of tau was attributed to its microtubule (MT)-binding domain, and homologous domains of MAP2 and MAP4 exhibit similar antagonistic activities. Taken together, the present results indicate that the level of Gem GTPase and its cell elongation activity are modulated by tau, and suggest that tau may be involved in a Gem GTPase-mediated signal transduction pathway.

Tau是一种主要的微管相关蛋白，参与神经细胞的形态发生和轴突的维持。Tau也是阿尔茨海默病患者大脑中发现的成对螺旋细丝的主要成分。为了探索tau在体内的未知作用，我们从tau缺陷的小鼠脑中提取了约11000个mRNAs，并与同龄对照脑中的mRNAs进行了比较。Gem GTPase是ras超家族的一种小的GTP结合蛋白，在8周龄时，tau基因缺陷小鼠脑内Gem GTP酶的表达显著增加。由于Gem GTPase是细胞骨架调节的Rho-Rho激酶途径的负调节因子，该蛋白在不表达tau的CHO细胞中瞬时过表达。Gem GTP酶的过表达导致CHO细胞显著延长，同时表达tau可消除这种作用，尽管tau不直接与Gem GTP酶结合。这种抗延伸活性归因于其微管(MT)结合域，MAP2和MAP4的同源结构域具有相似的拮抗活性。综上所述，这些结果表明Gem GTP酶的水平及其细胞伸长活性受tau的调控，提示tau可能参与了Gem GTP酶介导的信号转导途径。