Tau protein

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Tau proteins are microtubule-associated proteins found in neurons in the brain. They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University [Weingarten et al., 1975].

Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.

Six tau isoforms exist, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively-charged (allowing it to bind to the negatively-charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2,3, and 10 of the tau gene.

Phosphorylation of tau is regulated by a host of kinases. For example, PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization [Taniguchi et al., 2001].

Hyperphosphorylation of the tau protein (tau inclusions), however, results in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease and other tauopathies [Alonso et al., 2001].

Tau protein is a highly soluble microtubule-associated protein (MAP). One of its main functions is to stabilize axonal microtubules, which are essential for fast axonal transport. In humans, these proteins are mostly found in neurons compared to non-neuronal cells. The tau gene locates on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exon 2, 3 and 10 are alternative spliced, allowing six combinations (2-3-10-; 2+3-10-; 2+3+10-; 2-3-10+; 2+3-10+; 2+3+10+). Thus, in the human brain, the tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. They differ in either no, one or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-regions at the C-terminal part exon 10 missing. So, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total). All of the six tau isoforms are present in a hyperphosphorylated state in PHF from AD brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported.

References

Alonso, A. del C., Zaidi, T., Novak, M., Grundke-Iqbal, I., Iqbal, K. (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. PNAS. (98) 6923-8. http://www.pnas.org/cgi/content/full/98/12/6923

Delacourte, A. (2005) Tauopathies: recent insights into old diseases. Folia Neuropathol (43) 244-257. http://www.new.termedia.pl/magazine.php?magazine_id=20&article_id=5368&magazine_subpage=FULL_TEXT

Hirokawa, N., Shiomura, Y., Okabe, S. (1988) Tau proteins: the molecular structure and mode of binding on microtubules. J Cell Biol. (107) 1449-59. http://www.jcb.org/cgi/reprint/107/4/1449

Taniguchi, T., Kawamata, T., Mukai, H., Hasegawa, H., Isagawa, T., Yasuda, M., Hashimoto, T., Terashima, A., Nakai, M., Mori, H., Ono, Y., Tanaka, C. (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem. (276) 10025-31. http://www.jbc.org/cgi/content/full/276/13/10025

Weingarten, MD., Lockwood, AH., Hwo, SY., Kirschner, MW. (1975) A protein factor essential for microtubule assembly. PNAS. (72) 1858-1862. http://www.pnas.org/cgi/content/abstract/72/5/1858