It's all about tau

Abstract

Tau is a protein that is highly enriched in neurons and was originally defined by its ability to bind and stabilize microtubules. However, it is now becoming evident that the functions of tau extend beyond its ability to modulate microtubule dynamics. Tau plays a role in mediating axonal transport, synaptic structure and function, and neuronal signaling pathways. Although tau plays important physiological roles in neurons, its involvement in neurodegenerative diseases, and most prominently in the pathogenesis of Alzheimer disease (AD), has directed the majority of tau studies. However, a thorough knowledge of the physiological functions of tau and its post-translational modifications under normal conditions are necessary to provide the foundation for understanding its role in pathological settings. In this review, we will focus on human tau, summarizing tau structure and organization, as well as its posttranslational modifications associated with physiological processes. We will highlight possible mechanisms involved in mediating the turnover of tau and finally discuss newly elucidated tau functions in a physiological context.

Keywords: Axonal transport; Dendrites; Microtubules; Posttranslational modifications; Tau.

Figure 1.. Domains and alternative splicing of tau protein.

The MAPT (microtubule-associated protein tau) gene is situated on the long arm of chromosome 17 at band site 17q21 and encodes to six tau proteins as product of alternative splicing in the adult human brain. These isoforms are splicing variants of exons 2, 3 and 10. Tau may express no N-terminal inserts, just exon 2 or exons 2 and 3. Exon 10, which encodes a microtubule binding repeat sequence, can either be spliced in or out generating tau with 4 repeats or 3 repeats, respectively. S indicates a DNA sequence encoding the protein saithoin between exons 9 and 10.

Figure 2.. Post-translational modifications of tau.

Tau exhibits many different post-translational modifications including phosphorylation, glycosylation, acetylation, nitration, methylation, prolyl-isomerization, ubiquitylation, sumoylation and glycation. Phosphorylation is the most recurrent post-translational modification reported; however all these modifications can regulate tau binding to microtubules (MT), its metabolism, turnover or aggregation. Lower panel shows the tau sites that undergo post-translational modifications under physiological conditions.

Figure 3.. Physiological functions of tau.

Tau was initially identified as a protein that binds microtubules, and promotes microtubule polymerization and stability; however it is now evident that tau is a protein with multiple functions and that plays a number of different roles in cells including regulation of axonal transport, nuclear functions protecting DNA integrity; interactions with the actin cytoskeleton facilitating the formation of actin filaments; and regulation of NMDA receptor signaling through interactions with Fyn.