Tau protein

Source: Wikipedia, the free encyclopedia.
MAPT
Available structures
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000186868
ENSG00000276155
ENSG00000277956

ENSMUSG00000018411

UniProt

P10636

P10637

RefSeq (mRNA)

NM_001038609
NM_010838
NM_001285454
NM_001285455
NM_001285456

RefSeq (protein)
Location (UCSC)Chr 17: 45.89 – 46.03 MbChr 11: 104.23 – 104.33 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The tau proteins (abbreviated from tubulin associated unit

axons and are abundant in the neurons of the central nervous system (CNS), where the cerebral cortex has the highest abundance.[8] They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.[9]

Pathologies and

neurofibrillary tangles. The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly,[5][11] and since then they have been characterized as intrinsically disordered proteins.[12]

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. Image courtesy EnCor Biotechnology Inc
.

Function

Microtubule stabilization

Tau proteins are found more often in neurons than in non-neuronal cells in humans. One of tau's main functions is to modulate the stability of axonal

knockout mice that did not show abnormalities in brain development – possibly because of compensation in tau deficiency by other MAPs.[14][15][16]

Although tau is present in

axons, where it provides microtubule stabilization but also flexibility as needed. Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules.[11] Tau has two ways of controlling microtubule stability: isoforms and phosphorylation
.

In addition to its microtubule-stabilizing function, Tau has also been found to recruit signaling proteins and to regulate microtubule-mediated axonal transport.[18]

mRNA translation

Tau is a negative regulator of mRNA

rpS6.[22]

Behavior

The primary non-cellular functions of tau is to negatively regulate long-term memory[13] and to facilitate habituation (a form of non-associative learning),[13] two higher and more integrated physiological functions. Since regulation of tau is critical for memory, this could explain the linkage between tauopathies and cognitive impairment.

In mice, while the reported tau knockout strains present without overt phenotype when young,[14][23][24] when aged, they show some muscle weakness, hyperactivity, and impaired fear conditioning.[25] However, neither spatial learning in mice,[25][26][27] nor short-term memory (learning) in Drosophila[13] seems to be affected by the absence of tau.

In addition, tau knockout mice have abnormal sleep-wake cycle, with increased wakefulness periods and decreased non-rapid eye movements (NREM) sleep time.[28]

Other functions

Other typical functions of tau include

myelination or in brain insulin signaling, its role in the exposure to chronic stress and in depression
, etc.

Genetics

In humans, the MAPT gene for encoding tau protein is located on

C-terminal part (exon 10). Thus, 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 copies of the gene, resulting in congenital defects.[32][33][34][35]

Structure

Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding

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. 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.[36]

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.[37] Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[38] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[39] 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.[40] The binding of these phosphatases to tau affects tau's association with microtubules.

Phosphorylation of tau has also been suggested to be regulated by O-GlcNAc modification at various Ser and Thr residues.[41]

Mechanism

The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration.[42] The actual mechanism of how tau propagates from one cell to another is not well identified. Also, other mechanisms, including tau release and toxicity, are unclear. As tau aggregates, it replaces tubulin, which in turn enhances fibrilization of tau.[43] Several propagation methods have been proposed that occur by synaptic contact such as synaptic cell adhesion proteins, neuronal activity and other synaptic and non-synaptic mechanisms.[44] The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.[45][46]

Release

Tau involves in uptake and release process, which is known as seeding. Uptake of tau protein mechanism requires the presence of

hippocampal region in the early stages of the disease. They also suggested that microglia were also involved in the transport process, and their actual role is still unknown.[49]

Toxicity

Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanism such as

phosphoepitopes.[50] The degree of toxicity is affected by different factors, such as the degree of microtubule binding.[51][52] Toxicity could also happen by neurofibrillary tangles
(NFTs), which leads to cell death and cognitive decline.

Clinical significance

Further information: Tauopathy

synapses.[54]

Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.[55] Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.[56]

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 paired-helical-filament (PHF) tau and neurofibrillary tangles (NFTs).[57] The stage of the disease determines NFTs' phosphorylation. In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 199, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231.[58] Through its isoforms and phosphorylation, tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments
(PHFs) in the AD brain.

Tau mutations have many consequences, including microtubule dysfunction and alteration of the expression level of tau isoforms.

cytoplasmic functions and interferes with axonal transport, which can lead to cell death.[60][54]

Hyperphosphorylated forms of tau protein are the main component of PHFs of NFTs in the brain of AD patients. It has been well demonstrated that regions of tau six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK), can form tau PHF aggregation in AD. Apart from the PHF6, some other residue sites like Ser285, Ser289, Ser293, Ser305 and Tyr310, located near the C-terminal of the PHF6 sequences, play key roles in the phosphorylation of tau.

beta-amyloid, a component of the pathologic lesion seen in Alzheimer disease.[63][64] A recent hypothesis identifies the decrease of reelin signaling as the primary change in Alzheimer's disease that leads to the hyperphosphorylation of tau via a decrease in GSK3β inhibition.[65]

A68 is a name sometimes given (mostly in older publications) to the

hyperphosphorylated form of tau protein found in the brains of individuals with Alzheimer's disease.[66]

In 2020, researchers from two groups published studies indicating that an immunoassay blood test for the p-tau-217 form of the protein could diagnose Alzheimer's up to decades before dementia symptoms were evident.[67][68][69]

Traumatic brain injury

Repetitive mild

contact sports, especially American football,[70][71] and the concussive force of military blasts.[72] It can lead to chronic traumatic encephalopathy (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau.[73] After severe traumatic brain injury, high levels of tau protein in extracellular fluid in the brain are linked to poor outcomes.[74]

Prion-like propagation hypothesis

The term "prion-like" is often used to describe several aspects of tau pathology in various

PRNP, are also infectious with the capability to cross species. Since tau has yet to be proven to be infectious it is not considered to be a true prion but instead a "prion-like" protein. Much like true prions, pathological tau aggregates have been shown to have the capacity to induce misfolding of native tau protein.[76] Both misfolding competent and non-misfolding competent species of tau aggregates have been reported, indicating a highly specific mechanism.[77]

Interactions

Tau protein has been shown to

interact
with:

See also

References

  1. ^ a b c ENSG00000276155, ENSG00000277956 GRCh38: Ensembl release 89: ENSG00000186868, ENSG00000276155, ENSG00000277956 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018411 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^
    PMID 1057175
    .
  6. PMID 3131773
    .
  7. S2CID 19627629
    .
  8. PMID 35765081
    .
  9. PMID 1903170
    .
  10. PMID 20678581
    .
  11. ^
    PMID 599557
    .
  12. PMID 146092
    .
  13. ^
    PMID 31488613
    .
  14. ^
    S2CID 4322543
    .
  15. ^
    S2CID 32708424
    .
  16. PMID 22720190
    .
  17. S2CID 18776289
    .
  18. PMID 15642108
    .
  19. PMID 31268600
    .
  20. ^
    PMID 26791227
    .
  21. PMID 34147135
    .
  22. PMID 30759285
    .
  23. PMID 11228161
    .
  24. S2CID 25235996
    .
  25. ^
    S2CID 31204860
    .
  26. S2CID 32771613
    .
  27. PMID 20434528
    .
  28. PMID 20555133
    .
  29. PMID 29187252
    .
  30. PMID 3103857
    .
  31. PMID 15615637
    .
  32. S2CID 38047848
    .
  33. PMID 19165922
    .
  34. PMID 18648385
    .
  35. PMID 16042549
    .
  36. PMID 9169588
    .
  37. PMID 11104762
    .
  38. S2CID 94265621
    .
  39. PMID 7983034
    .
  40. S2CID 40592137
    .
  41. PMID 15249677
    .
  42. PMID 8990203
    .
  43. PMID 19282288
    .
  44. PMID 25981034
    .
  45. PMID 30580037
    .
  46. PMID 30823892
    .
  47. PMID 28772101
    .
  48. PMID 29238289
    .
  49. PMID 26436904
    .
  50. S2CID 18896805
    .
  51. PMID 18930955
    .
  52. PMID 15823754
    .
  53. PMID 11381127
    .
  54. ^ a b "Alzheimer's Brain Tangles." Alzheimer's Association, www.alz.org/braintour/tangles.asp.
  55. PMID 27878758
    .
  56. PMID 22561167
    .
  57. PMID 19742193
    .
  58. S2CID 6799990
    .
  59. S2CID 38730940
    .
  60. S2CID 37380445
    .
  61. PMID 30893872
    .
  62. PMID 25339173
    .
  63. PMID 8393578
    .
  64. S2CID 23900723
    .
  65. PMID 35008886
    .
  66. ^ "A68", The Free Dictionary, retrieved 2020-01-27
  67. ISSN 0362-4331
    . Retrieved 2020-07-29.
  68. PMID 32725127
    .
  69. PMID 32722745
    .
  70. ^ "Brain Trauma". NOVA. PBS Online by WGBH.
  71. S2CID 196391183
    .
  72. PMID 22593173
    .
  73. PMID 23208308
    .
  74. PMID 22116192
    .
  75. S2CID 211475911
    , retrieved 2021-03-18
  76. PMID 24493463
    .
  77. PMID 31257249
    .
  78. PMID 10464279
    .
  79. S2CID 9086733
    .
  80. PMID 11826099
    .
  81. PMID 11264299
    .
  82. PMID 2833519
    .
  83. PMID 10840038
    .

Further reading

External links

Wikimedia Commons has media related to Tau proteins.
Look up tau protein or tau in Wiktionary, the free dictionary.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Tau_protein&oldid=1220837020"