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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 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 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 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.


Further reading

  • Goedert M, Crowther RA, Garner CC (1991). "Molecular characterization of microtubule-associated proteins tau and MAP2". Trends Neurosci. 14 (5): 193-9.
  • Morishima-Kawashima M, Hasegawa M, Takio K, et al. (1995). "Hyperphosphorylation of tau in PHF". Neurobiol. Aging 16 (3): 365–71; discussion 371-80.
  • Heutink P (2000). "Untangling tau-related dementia". Hum. Mol. Genet. 9 (6): 979-86.
  • Goedert M, Spillantini MG (2000). "Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease". Biochim. Biophys. Acta 1502 (1): 110-21.
  • Morishima-Kawashima M, Ihara Y (2002). "[Recent advances in Alzheimer's disease]". Seikagaku 73 (11): 1297-07.
  • Blennow K, Vanmechelen E, Hampel H (2002). "CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease". Mol. Neurobiol. 24 (1-3): 87–97.
  • Ingram EM, Spillantini MG (2003). "Tau gene mutations: dissecting the pathogenesis of FTDP-17". Trends in molecular medicine 8 (12): 555-62.
  • Pickering-Brown S (2004). "The tau gene locus and frontotemporal dementia". Dementia and geriatric cognitive disorders 17 (4): 258-60.
  • van Swieten JC, Rosso SM, van Herpen E, et al. (2004). "Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17". Dementia and geriatric cognitive disorders 17 (4): 261-4.
  • Kowalska A, Jamrozik Z, Kwieciński H (2004). "Progressive supranuclear palsy--parkinsonian disorder with tau pathology". Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences 42 (2): 119–23.
  • Rademakers R, Cruts M, van Broeckhoven C (2005). "The role of tau (MAPT) in frontotemporal dementia and related tauopathies". Hum. Mutat. 24 (4): 277-95.
  • Lee HG, Perry G, Moreira PI, et al. (2005). "Tau phosphorylation in Alzheimer's disease: pathogen or protector?". Trends in molecular medicine 11 (4): 164-9.
  • Hardy J, Pittman A, Myers A, et al. (2005). "Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens". Biochem. Soc. Trans. 33 (Pt 4): 582-5. . 
  • Deutsch SI, Rosse RB, Lakshman RM (2007). "Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications". Prog. Neuropsychopharmacol. Biol. Psychiatry 30 (8): 1369-80.
  • Williams DR (2006). "Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau". Internal medicine journal 36 (10): 652-60.
  • Pittman AM, Fung HC, de Silva R (2006). "Untangling the tau gene association with neurodegenerative disorders". Hum. Mol. Genet. 15 Spec No 2: R188-95.
  • Roder HM, Hutton ML (2007). "Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease". Expert Opin. Ther. Targets 11 (4): 435-42.  
  • van Swieten J, Spillantini MG (2007). "Hereditary frontotemporal dementia caused by Tau gene mutations". Brain Pathol. 17 (1): 63-73.
  • Caffrey TM, Wade-Martins R (2007). "Functional MAPT haplotypes: bridging the gap between genotype and neuropathology". Neurobiol. Dis. 27 (1): 1-10.
  • 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.
  • 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
  • Dual modification of Alzheimers disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach Stefani N. Thomas,1 Kristen E. Funk,2 Yunhu Wan,3 Zhongping Liao,4 Peter Davies,5 Jeff Kuret,corresponding author2 and Austin J. Yang, Acta Neuropathol. 2012 January; 123(1): 105117.
  • What Does Tau Protein Have to Do with Football, Dementia, and Suicide?


  1. Klein, Corinna; Kramer Eva-Maria, Cardine Anne-Marie, Schraven Burkhardt, Brandt Roland, Trotter Jacqueline (Feb. 2002). "Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau". J. Neurosci. (United States) 22 (3): 698-707.
  2. Jensen, P H; Hager H, Nielsen M S, Hojrup P, Gliemann J, Jakes R (Sep. 1999). "alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356". J. Biol. Chem. (UNITED STATES) 274 (36): 25481-9.
  3. Hashiguchi, M; Sobue K, Paudel H K (Aug. 2000). "14-3-3zeta is an effector of tau protein phosphorylation". J. Biol. Chem. (UNITED STATES) 275 (33): 25247-54.
  4. Yu, W H; Fraser P E (Apr. 2001). "S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease". J. Neurosci. (United States) 21 (7): 2240-6.
  5. Baudier, J; Cole R D (Apr. 1988). "Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II". J. Biol. Chem. (UNITED STATES) 263 (12): 5876-83.


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