Microtubule-associated protein tau in development, degeneration and protection of neurons
Section snippets
Polymorphism of tau gene and proteins
Tau is a major microtubule-associated protein, which was discovered, purified and characterized as a microtubule assembly-promoting factor by groups of Kirschner and Nunez (Cleveland et al., 1977, Fellous et al., 1977, Weingarten et al., 1975). A cDNA for tau was first isolated from a mouse brain expression library (Lee et al., 1988), and subsequently, it was cloned and sequenced in a number of distinct species, including human (Goedert et al., 1989a, Himmler, 1989). The human tau gene, located
The biological functions of tau proteins
The tau proteins in the brain have been structurally divided into two large domains: the projection domain covers the amino-terminal two-third of the molecule and the microtubule-binding domain covers the carboxyl-terminal one-third of the molecule. In each domain, there are motifs that endow tau with the characteristics and functions. The major biological function of tau is to promote microtubule assembly and maintain the stability of the previously formed microtubules, which are essential for
Posttranslational modifications of tau and the effects
During normal development, tau protein undergoes various posttranslational modifications, including phosphorylation, glycosylation, glycation, ubiquitination, truncation, nitration, etc. (see Fig. 1). As an increased amount of the modified tau has been found in a large number of neurodegenerative disorders, the study of tau modifications and the effects on the function of tau have caught great attention. Except glycation, the other modifications of tau protein can be also detected, though at a
Regulation of tau phosphorylation
Among the above-mentioned posttranslational modifications, tau phosphorylation has been studied most extensively. Tau hyperphosphorylation is a result of an imbalanced regulation of protein kinases and protein phosphatases. Although, Tyr18 (Lee et al., 2004) and Tyr394 (Noble et al., 2004) phosphorylated tau have been recently detected in AD brains, the known function-associated phosphorylation sites of tau are reportedly only on serine and threonine, suggesting the crucial role of serine and
Tau hyperphosphorylation in neurodegeneration
It is widely recognized that tau hyperphosphorylation is an early event of neurodegeneration and it may play a crucial detrimental role in accelerating the disease processes. Nonetheless, it is still not fully understood how tau hyperphosphorylation contributes to neurodegeneration.
Tau models
Several tau transgenic models have been established since 1995 (for review, see Götz et al., 2007). The general information for these transgenic mice is summarized in Table 2.
Future perspectives and challenges
Although tau has been recognized for over 30 years, and extensive efforts have been made to explore the roles of tau proteins in physiological functions and in tauopathies, further studies should be of great significance for our current understanding of tau in normal neural development and pathological conditions. The following issues have caught our attention.
Acknowledgements
I would like to thank Y.H. Liu, Q. Tian, J.Y. Zhang, L.Q. Zhu, Y. Wang and J. Yin for their editorial help and proofreading of the manuscript. The work from our group is supported in part by the National Natural Science Foundation of China (30430270, 30328007, and 39925012) and the National Science and Technology Committee of China (G1999054000, 2006CB500703, and 2006AA02Z4A1).
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