Tau protein

Tau proteins are microtubule-associated proteins that are abundant in neurons in the central nervous system and are less common elsewhere. They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University [http://www.pnas.org/cgi/content/abstract/72/5/1858 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 in brain tissue, 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 [http://www.jbc.org/cgi/content/full/276/13/10025 Taniguchi "et al"., 2001] .

Hyperphosphorylation of the tau protein (tau inclusions), however, can result 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 [http://www.pnas.org/cgi/content/full/98/12/6923 Alonso "et al"., 2001] .

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are mostly found in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with STOP proteins in the proximal portions of axons which essentially lock down the microtubules and MAP2 that stabilizes microtubules in dendrites. 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 an often hyperphosphorylated state in paired helical filaments from Alzheimer's Disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.

ee also

* Alzheimer's Disease
* Proteopathy

Further reading

PBB_Further_reading
citations =
*cite journal | author=Goedert M, Crowther RA, Garner CC |title=Molecular characterization of microtubule-associated proteins tau and MAP2 |journal=Trends Neurosci. |volume=14 |issue= 5 |pages= 193–9 |year= 1991 |pmid= 1713721 |doi=10.1016/0166-2236(91)90105-4
*cite journal | author=Morishima-Kawashima M, Hasegawa M, Takio K, "et al." |title=Hyperphosphorylation of tau in PHF |journal=Neurobiol. Aging |volume=16 |issue= 3 |pages= 365–71; discussion 371–80 |year= 1995 |pmid= 7566346 |doi=10.1016/0197-4580(95)00027-C
*cite journal | author=Heutink P |title=Untangling tau-related dementia |journal=Hum. Mol. Genet. |volume=9 |issue= 6 |pages= 979–86 |year= 2000 |pmid= 10767321 |doi=10.1093/hmg/9.6.979
*cite journal | author=Goedert M, Spillantini MG |title=Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease |journal=Biochim. Biophys. Acta |volume=1502 |issue= 1 |pages= 110–21 |year= 2000 |pmid= 10899436 |doi=
*cite journal | author=Morishima-Kawashima M, Ihara Y |title= [Recent advances in Alzheimer's disease] |journal=Seikagaku |volume=73 |issue= 11 |pages= 1297–307 |year= 2002 |pmid= 11831025 |doi=
*cite journal | author=Blennow K, Vanmechelen E, Hampel H |title=CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease |journal=Mol. Neurobiol. |volume=24 |issue= 1-3 |pages= 87–97 |year= 2002 |pmid= 11831556 |doi=10.1385/MN:24:1-3:087
*cite journal | author=Ingram EM, Spillantini MG |title=Tau gene mutations: dissecting the pathogenesis of FTDP-17 |journal=Trends in molecular medicine |volume=8 |issue= 12 |pages= 555–62 |year= 2003 |pmid= 12470988 |doi=10.1016/S1471-4914(02)02440-1
*cite journal | author=Pickering-Brown S |title=The tau gene locus and frontotemporal dementia |journal=Dementia and geriatric cognitive disorders |volume=17 |issue= 4 |pages= 258–60 |year= 2004 |pmid= 15178931 |doi= 10.1159/000077149
*cite journal | author=van Swieten JC, Rosso SM, van Herpen E, "et al." |title=Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17 |journal=Dementia and geriatric cognitive disorders |volume=17 |issue= 4 |pages= 261–4 |year= 2004 |pmid= 15178932 |doi= 10.1159/000077150
*cite journal | author=Kowalska A, Jamrozik Z, Kwieciński H |title=Progressive supranuclear palsy--parkinsonian disorder with tau pathology |journal=Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences |volume=42 |issue= 2 |pages= 119–23 |year= 2004 |pmid= 15266787 |doi=
*cite journal | author=Rademakers R, Cruts M, van Broeckhoven C |title=The role of tau (MAPT) in frontotemporal dementia and related tauopathies |journal=Hum. Mutat. |volume=24 |issue= 4 |pages= 277–95 |year= 2005 |pmid= 15365985 |doi= 10.1002/humu.20086
*cite journal | author=Lee HG, Perry G, Moreira PI, "et al." |title=Tau phosphorylation in Alzheimer's disease: pathogen or protector? |journal=Trends in molecular medicine |volume=11 |issue= 4 |pages= 164–9 |year= 2005 |pmid= 15823754 |doi= 10.1016/j.molmed.2005.02.008
*cite journal | author=Hardy J, Pittman A, Myers A, "et al." |title=Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens |journal=Biochem. Soc. Trans. |volume=33 |issue= Pt 4 |pages= 582–5 |year= 2005 |pmid= 16042549 |doi= 10.1042/BST0330582
*cite journal | author=Deutsch SI, Rosse RB, Lakshman RM |title=Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=30 |issue= 8 |pages= 1369–80 |year= 2007 |pmid= 16793187 |doi= 10.1016/j.pnpbp.2006.04.007
*cite journal | author=Williams DR |title=Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau |journal=Internal medicine journal |volume=36 |issue= 10 |pages= 652–60 |year= 2006 |pmid= 16958643 |doi= 10.1111/j.1445-5994.2006.01153.x
*cite journal | author=Pittman AM, Fung HC, de Silva R |title=Untangling the tau gene association with neurodegenerative disorders |journal=Hum. Mol. Genet. |volume=15 Spec No 2 |issue= |pages= R188–95 |year= 2006 |pmid= 16987883 |doi= 10.1093/hmg/ddl190
*cite journal | author=Roder HM, Hutton ML |title=Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease |journal=Expert Opin. Ther. Targets |volume=11 |issue= 4 |pages= 435–42 |year= 2007 |pmid= 17373874 |doi= 10.1517/14728222.11.4.435
*cite journal | author=van Swieten J, Spillantini MG |title=Hereditary frontotemporal dementia caused by Tau gene mutations |journal=Brain Pathol. |volume=17 |issue= 1 |pages= 63–73 |year= 2007 |pmid= 17493040 |doi= 10.1111/j.1750-3639.2007.00052.x
*cite journal | author=Caffrey TM, Wade-Martins R |title=Functional MAPT haplotypes: bridging the gap between genotype and neuropathology |journal=Neurobiol. Dis. |volume=27 |issue= 1 |pages= 1–10 |year= 2007 |pmid= 17555970 |doi= 10.1016/j.nbd.2007.04.006
*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

External links

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