Identification of novel genes closely related to Alzheimer's disease

Tau是一种主要的微管相关蛋白，参与神经元细胞的形态发生和轴突的维持。Tau也是在受阿尔茨海默病影响的大脑中发现的成对螺旋丝的主要成分。为了探索tau蛋白在体内尚未确定的作用，从tau蛋白缺陷小鼠大脑中分析了约11，000个mRNA，并与相同年龄的对照大脑进行了比较。Gem GT3（ras超家族的一种小GTP结合蛋白）的表达在8周龄tau缺陷小鼠的脑中显著增加。由于Gem GTPase是细胞骨架调节的Rho-Rho激酶途径的负调节因子，因此该蛋白质在不表达tau的CHO细胞中短暂过表达。Gem GT3的过表达诱导CHO细胞的显著伸长，并且tau的同时表达消除了这种效应，尽管tau不直接与Gem GT3结合。tau蛋白的这种抗延伸活性归因于其微管（MT）结合结构域，并且MAP 2和MAP 4的同源结构域表现出类似的拮抗活性。两者合计，目前的结果表明，Gem GTP酶的水平和它的细胞伸长活性的调节tau，并建议，tau可能参与Gem GTP酶介导的信号转导途径。

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.