Tau protein

Microtubule-associated protein tau
Rendering of a fragment of MAPT bound to the WW domain of the PIN1 protein from PDB 1I8H​
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1I8H​, 2ON9​, 3OVL​, 4E0M​, 4E0N​, 4E0O​, 4FL5​, 4GLR​, 4NP8​
Identifiers
Symbols	MAPT ; DDPAC; FTDP-17; MAPTL; MSTD; MTBT1; MTBT2; PPND; PPP1R103; TAU
External IDs	OMIM: 157140 HomoloGene: 74962 ChEMBL: 1293224 GeneCards: MAPT Gene
Gene ontology Molecular function • structural constituent of cytoskeleton • protein binding • microtubule binding • SH3 domain binding • enzyme binding • protein kinase binding • apolipoprotein binding • protein phosphatase 2A binding • lipoprotein particle binding Cellular component • cytosol • microtubule • microtubule associated complex • plasma membrane • axoneme • postsynaptic density • axon • growth cone • nuclear periphery • cytoplasmic ribonucleoprotein granule • tubulin complex Biological process • microtubule cytoskeleton organization • neuron migration • apoptotic process • cellular component disassembly involved in execution phase of apoptosis • brain development • female pregnancy • response to nutrient • adult walking behavior • axon cargo transport • intrinsic apoptotic signaling pathway in response to oxidative stress • response to organic substance • regulation of autophagy • programmed cell death • regulation of microtubule polymerization • positive regulation of microtubule polymerization • negative regulation of intracellular transport • positive regulation of axon extension • mitochondrion transport along microtubule • axon extension • generation of neurons • regulation of microtubule-based movement Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4137	17762
Ensembl	ENSG00000186868	ENSMUSG00000018411
UniProt	P10636	P10637
RefSeq (mRNA)	NM_001123066	NM_001038609
RefSeq (protein)	NP_001116538	NP_001033698
Location (UCSC)	Chr 17: 45.89 – 46.03 Mb	Chr 11: 104.23 – 104.33 Mb
PubMed search

Tau proteins (or τ proteins, after the Greek letter by that name) are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.^[1] Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease ^[2] are associated with tau proteins that have become defective and no longer stabilize microtubules properly.

The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau) and is located on chromosome 17.^[3][4] They were discovered in 1975 in Marc Kirschner's laboratory at Princeton University.^[5]

Neurons were grown in tissue culture and stained with antibody to MAP2 protein in green and MAP tau in red using the immunofluorescence technique. MAP2 is found only in dendrites and perikarya, while tau is found not only in the dendrites and perikarya but also in axons. As a result axons appear red while the dendrites and perikarya appear yellow, due to superimposition of the red and green signals. DNA is shown in blue using the DAPI stain which highlights the nuclei.

Function

Tau protein is a highly soluble microtubule-associated protein (MAP). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knockout mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs.^[6] 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 MAP6 (STOP) proteins in the proximal portions of axons, which, in essence, lock down the microtubules and MAP2 that stabilizes microtubules in dendrites.

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.

Structure

Six tau isoforms exist in human 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.

Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.^[7]

Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.^[8]

Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.^[9] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.^[10] Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396.^[11] The binding of these phosphatases to tau affects tau's association with MTs.

Genetics

In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively 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 zero, 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).

The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copy of the gene, resulting in congenital defects.^{[12][13][14][15]}

Clinical significance

Hyperphosphorylation of the tau protein (tau inclusions, pTau) 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, frontotemporal dementia, and other tauopathies.^[16]

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.

Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer's disease.^[17][18]

Some aspects of how the disease functions also suggests that it has some similarities to prion proteins.^[19]

Traumatic brain injury

High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.^[20]

Tau Hypothesis of Alzheimer's Disease

The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs (neurofibrillary tangles). Tau protein is a highly soluble microtubule-associated protein (MAP). Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. Tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. The longest isoform in the CNS has four repeats (R1, R2, R3, and R4) and two inserts (441 amino acids total), whereas 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 AD.

Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans.[6] Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAP 1(microtubule associated protein1), MAP 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.^[21]

Interactions

Tau protein has been shown to interact with proto-oncogene tyrosine-protein kinase:

• Alpha-synuclein,^[22][23]
• FYN,^[24]
• S100B,^[25][26] and
• YWHAZ.^[27]

See also

• Tauopathy, a class of diseases associated with accumulated tau proteins
• Dementia pugilistica
• Alzheimer's disease
• Corticobasal degeneration
• Progressive supranuclear palsy
• Proteopathy
• Pick's disease
• Frontotemporal dementia and parkinsonism linked to chromosome 17
• Prion

References

Further reading

External links

• tau Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
• GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders
• MR scans of variant CJD CSF Tau positive man