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词条 Tau protein
释义

  1. Function

  2. Genetics

  3. Structure

  4. Tau Mechanism

      Tau release    Tau toxicity  

  5. Clinical significance

  6. Traumatic brain injury

  7. Tau hypothesis of Alzheimer's disease

  8. Interactions

  9. See also

  10. References

  11. Further reading

  12. External links

{{Infobox_gene}}

Tau proteins (or τ proteins, after the Greek letter with 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]

The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly [5][6] and since then, they have been characterized as intrinsically disordered proteins.[7]

Function

Tau protein is a highly soluble microtubule-associated protein tau (MAPT). 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 knock out mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs.[8] 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. In addition to their microtubule stabilizing functions, MAPTs have also been found to recruit signaling proteins and regulation of microtubule-mediated transport.[9]

Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules.[6] Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.

Genetics

In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons.[10] The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively spliced that lead to formation of six tau isoforms.[11] In human brain, tau proteins constitute a family of six isoforms with a range of 352-441 amino acids. Tau isoforms are different 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). 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.[12][13][14][15]

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.[16]

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.[17] Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[18] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[19] 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.[20] The binding of these phosphatases to tau affects tau's association with MTs.

Tau Mechanism

The accumulation of hyperphosphorylated tau in neurons will lead to the neurofibrillary degeneration.[21] The actual mechanism of how tau propagate 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 enhance fibrilization of tau.[22] Several propagation methods have been proposed which occur by synaptic contact such as synaptic cell adhesion proteins and neuronal activity and other synaptic and non-synaptic mechanisms.[23] The mechanism of tau aggregation is still not completely elucidated still there are several factors that favorize this process, including Tau phosphorylation and zinc ions.[24][25]

Tau release

Tau involves in uptake and release process, which is known as seeding. Uptake of tau protein mechanism requires the presence of heparan sulfate proteoglycans at the cell surface which happen by macropinocytosis.[26] On the other hand, tau release depends on neuronal activity. Many factors influence tau release, for example, type of isoforms or MAPT mutations which change the extracellular level of tau.[27] According to Asai and his colleagues, spreading of tau protein occurs from entorhinal cortex to the 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.[28]

Tau toxicity

Tau causes toxic effects through its accumulation inside cells. Many enzymes involved in toxicity mechanism such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn lead to activate other kinases (GSK-3 and Cdk5) that cause disease-associated phophoepitopes.[29] The degree of toxicity is affected by different factors such as the degree of microtubule binding.[30][31] Toxicity could also happen by NFTs which lead to cell death and cognitive decline.

Clinical significance

{{Further|Tauopathy}}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.[32]

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.

Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses. Tangles are clumps of Tau protein that stick together and block essential nutrients that need to be distributed to cells in the brain, causing the cells to die.[33]

Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer's disease.[34][35]

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.[36]

Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.[37]

Traumatic brain injury

Repetitive mild traumatic brain injury (TBI) is now recognized as a central component of brain injury in contact sports, especially American football,[38][39] and the concussive force of military blasts.[40] It can lead to chronic traumatic encephalopathy (CTE) that is characterized by fibrillar tangles of hyperphosphorylated tau.[41]

High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.[42]

Concussions increase the speed of cognitive decline which is caused by a degradation in the brain from the Tau protein.[43]

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) [44]. The stage of the disease determines NFTs phosphorylation. In AD, at least 19 amino acids are phosphorylated such as pre-NFTs phosphorylation occurs at serine 119, 202, and 409. While intra-NFT phosphorylation happens at serine 396 and threonine 231.[45] Tau protein is a highly soluble microtubule-associated protein tau (MAPT).[6] 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 from AD.

Tau mutations have many consequences such as changing the expression level of tau isoforms or lead to MTs dysfunction.[46] 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, MAPT 1(microtubule associated protein tau1), MAPT 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.[47]

Vaccines have been found that attack the Tau protein, one of the leading causes of Alzheimer's. This would reduce symptoms for those with Alzheimer's disease and could eventually lead to a cure.[48]

Interactions

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

  • Alpha-synuclein,[49][50]
  • FYN,[51]
  • S100B,[52][53] and
  • YWHAZ.[54]

See also

{{col div|colwidth=30em}}
  • Tauopathy, a class of diseases associated with accumulated tau proteins
  • Dementia pugilistica
  • Alzheimer's disease
  • Primary age-related tauopathy
  • Aging-related tau astrogliopathy
  • Corticobasal degeneration
  • Progressive supranuclear palsy
  • Proteopathy
  • Pick's disease
  • Frontotemporal dementia and parkinsonism linked to chromosome 17
  • Prion
{{colend}}

References

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50. ^{{cite journal | vauthors = Giasson BI, Lee VM, Trojanowski JQ | title = Interactions of amyloidogenic proteins | journal = Neuromolecular Medicine | volume = 4 | issue = 1–2 | pages = 49–58 | year = 2003 | pmid = 14528052 | doi = 10.1385/NMM:4:1-2:49 }}
51. ^{{cite journal | vauthors = Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J | title = Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau | journal = The Journal of Neuroscience | volume = 22 | issue = 3 | pages = 698–707 | date = February 2002 | pmid = 11826099 | doi = 10.1523/JNEUROSCI.22-03-00698.2002}}
52. ^{{cite journal | vauthors = Yu WH, Fraser PE | title = S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease | journal = The Journal of Neuroscience | volume = 21 | issue = 7 | pages = 2240–6 | date = April 2001 | pmid = 11264299 | doi = 10.1523/JNEUROSCI.21-07-02240.2001}}
53. ^{{cite journal | vauthors = Baudier J, Cole RD | title = Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II | journal = The Journal of Biological Chemistry | volume = 263 | issue = 12 | pages = 5876–83 | date = April 1988 | pmid = 2833519 | doi = }}
54. ^{{cite journal | vauthors = Hashiguchi M, Sobue K, Paudel HK | title = 14-3-3zeta is an effector of tau protein phosphorylation | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25247–54 | date = August 2000 | pmid = 10840038 | doi = 10.1074/jbc.M003738200 }}

Further reading

{{refbegin | colwidth=35em}}
  • {{cite journal | vauthors = Goedert M, Crowther RA, Garner CC | title = Molecular characterization of microtubule-associated proteins tau and MAP2 | journal = Trends in Neurosciences | volume = 14 | issue = 5 | pages = 193–9 | date = May 1991 | pmid = 1713721 | doi = 10.1016/0166-2236(91)90105-4 }}
  • {{cite journal | vauthors = Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y | title = Hyperphosphorylation of tau in PHF | journal = Neurobiology of 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 | vauthors = Heutink P | title = Untangling tau-related dementia | journal = Human Molecular Genetics | volume = 9 | issue = 6 | pages = 979–86 | date = April 2000 | pmid = 10767321 | doi = 10.1093/hmg/9.6.979 }}
  • {{cite journal | vauthors = Goedert M, Spillantini MG | title = Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease | journal = Biochimica et Biophysica Acta | volume = 1502 | issue = 1 | pages = 110–21 | date = July 2000 | pmid = 10899436 | doi = 10.1016/S0925-4439(00)00037-5 }}
  • {{cite journal | vauthors = Morishima-Kawashima M, Ihara Y | title = [Recent advances in Alzheimer's disease] | journal = Seikagaku. The Journal of Japanese Biochemical Society | volume = 73 | issue = 11 | pages = 1297–307 | date = November 2001 | pmid = 11831025 | doi = }}
  • {{cite journal | vauthors = Blennow K, Vanmechelen E, Hampel H | title = CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease | journal = Molecular Neurobiology | volume = 24 | issue = 1–3 | pages = 87–97 | year = 2002 | pmid = 11831556 | doi = 10.1385/MN:24:1-3:087 }}
  • {{cite journal | vauthors = 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 | date = December 2002 | pmid = 12470988 | doi = 10.1016/S1471-4914(02)02440-1 }}
  • {{cite journal | vauthors = 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 | vauthors = van Swieten JC, Rosso SM, van Herpen E, Kamphorst W, Ravid R, Heutink P | 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 | vauthors = Kowalska A, Jamrozik Z, Kwieciński H | title = Progressive supranuclear palsy--parkinsonian disorder with tau pathology | journal = Folia Neuropathologica | volume = 42 | issue = 2 | pages = 119–23 | year = 2004 | pmid = 15266787 | doi = }}
  • {{cite journal | vauthors = Rademakers R, Cruts M, van Broeckhoven C | title = The role of tau (MAPT) in frontotemporal dementia and related tauopathies | journal = Human Mutation | volume = 24 | issue = 4 | pages = 277–95 | date = October 2004 | pmid = 15365985 | doi = 10.1002/humu.20086 }}
  • {{cite journal | vauthors = Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA | title = Tau phosphorylation in Alzheimer's disease: pathogen or protector? | journal = Trends in Molecular Medicine | volume = 11 | issue = 4 | pages = 164–9 | date = April 2005 | pmid = 15823754 | doi = 10.1016/j.molmed.2005.02.008 }}
  • {{cite journal | vauthors = Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, Hutton M, Duckworth J | title = Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 4 | pages = 582–5 | date = August 2005 | pmid = 16042549 | doi = 10.1042/BST0330582 }}
  • {{cite journal | vauthors = 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 = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 30 | issue = 8 | pages = 1369–80 | date = December 2006 | pmid = 16793187 | doi = 10.1016/j.pnpbp.2006.04.007 }}
  • {{cite journal | vauthors = 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 | date = October 2006 | pmid = 16958643 | doi = 10.1111/j.1445-5994.2006.01153.x }}
  • {{cite journal | vauthors = Pittman AM, Fung HC, de Silva R | title = Untangling the tau gene association with neurodegenerative disorders | journal = Human Molecular Genetics | volume = 15 Spec No 2 | issue = Review Issue 2 | pages = R188–95 | date = October 2006 | pmid = 16987883 | doi = 10.1093/hmg/ddl190 | series = 15 }}
  • {{cite journal | vauthors = Roder HM, Hutton ML | title = Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease | journal = Expert Opinion on Therapeutic Targets | volume = 11 | issue = 4 | pages = 435–42 | date = April 2007 | pmid = 17373874 | doi = 10.1517/14728222.11.4.435 }}
  • {{cite journal | vauthors = van Swieten J, Spillantini MG | title = Hereditary frontotemporal dementia caused by Tau gene mutations | journal = Brain Pathology | volume = 17 | issue = 1 | pages = 63–73 | date = January 2007 | pmid = 17493040 | doi = 10.1111/j.1750-3639.2007.00052.x }}
  • {{cite journal | vauthors = Caffrey TM, Wade-Martins R | title = Functional MAPT haplotypes: bridging the gap between genotype and neuropathology | journal = Neurobiology of Disease | volume = 27 | issue = 1 | pages = 1–10 | date = July 2007 | pmid = 17555970 | pmc = 2801069 | doi = 10.1016/j.nbd.2007.04.006 }}
  • {{cite journal | vauthors = Delacourte A | title = Tauopathies: recent insights into old diseases | journal = Folia Neuropathologica | volume = 43 | issue = 4 | pages = 244–57 | year = 2005 | pmid = 16416389 | doi = }}
  • {{cite journal | vauthors = Hirokawa N, Shiomura Y, Okabe S | title = Tau proteins: the molecular structure and mode of binding on microtubules | journal = The Journal of Cell Biology | volume = 107 | issue = 4 | pages = 1449–59 | date = October 1988 | pmid = 3139677 | pmc = 2115262 | doi = 10.1083/jcb.107.4.1449 }}
{{refend}}

External links

  • {{MeshName|tau+Proteins}}
  • [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ftdp-17 GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders]
  • [https://web.archive.org/web/20131203022442/http://rad.usuhs.edu/medpix/kiosk_image.html?mode=pt&pt_id=13421#pic MR scans of variant CJD] CSF Tau positive man
{{Cytoskeletal Proteins}}{{DEFAULTSORT:Tau Protein}}

1 : Proteins
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