Tau protein

From Wikipedia, the free encyclopedia
Jump to navigation Jump to search
MAPT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMAPT, DDPAC, FTDP-17, MAPTL, MSTD, MTBT1, MTBT2, PPND, PPP1R103, TAU, microtubule associated protein tau, Tau proteins
External IDsOMIM: 157140 MGI: 97180 HomoloGene: 74962 GeneCards: MAPT
Gene location (Human)
Chromosome 17 (human)
Chr.Chromosome 17 (human)[1]
Chromosome 17 (human)
Genomic location for MAPT
Genomic location for MAPT
Band17q21.31Start45,894,382 bp[1]
End46,028,334 bp[1]
RNA expression pattern
PBB GE MAPT 203928 x at fs.png

PBB GE MAPT 203929 s at fs.png

PBB GE MAPT 203930 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001038609
NM_010838
NM_001285454
NM_001285455
NM_001285456

RefSeq (protein)

NP_001033698
NP_001272383
NP_001272384
NP_001272385
NP_034968

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 (or τ proteins, after the Greek letter with that name) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene MAPT (microtubule-associated protein tau).[5][6] They have roles primarily in maintaining the stability of microtubules in axons and are abundant in the neurons of the central nervous system (CNS). They are less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.[7]

Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease[8] are associated with tau proteins that have become hyperphosphorylated insoluble aggregates called neurofibrillary tangles. The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly,[9][10] and since then they have been characterized as intrinsically disordered proteins.[11]

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. Image courtesy EnCor Biotechnology Inc.

Function[edit]

Microtubule stabilization[edit]

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 microtubules.[10][12] Other nervous system microtubule-associated proteins (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.[13][14][15]

Although tau is present in dendrites at low levels, where it is involved in postsynaptic scaffolding,[16] it is active primarily in the distal portions of 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.[10] 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.[17]

Protein translation[edit]

Tau is a negative regulator of protein translation in both Drosophila[12] and human[18] brains, through its binding to ribosomes, which results in impaired ribosomal function, reduction of protein synthesis and altered synaptic function.[12][18] Tau interacts specifically with several ribosomal proteins, including the crucial regulator of translation rpS6.[19]

Behavior[edit]

The primary non-cellular function of tau is to negatively regulate long-term memory[12] and to facilitate habituation (a form of non-associative learning),[12] 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,[13][20][21] when aged, they show some muscle weakness, hyperactivity and impaired fear conditioning.[22] However, neither spatial learning in mice,[22][23][24] nor short-term memory (learning) in Drosophila[12] 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.[25]

Other functions[edit]

Other typical functions of tau include cellular signalling, neuronal development, neuroprotection and apoptosis.[26] Atypical, non-standard roles of tau[27] are also under current investigation, such as its involvement in chromosome stability, its interaction with the cellular transcriptome, its interaction with other cytoskeletal or synaptic proteins, its involvement in myelination or in brain insulin signaling, its role in the exposure to chronic stress and in depression, etc.

Genetics[edit]

In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons.[28] 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.[29] 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.[30][31][32][33]

Structure[edit]

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. 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.[34]

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.[35] Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[36] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[37] 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.[38] 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.[39]

Mechanism[edit]

The accumulation of hyperphosphorylated tau in neurons is associated with neurofibrillary degeneration.[40] 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.[41] 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.[42] The mechanism of tau aggregation is still not completely elucidated, but several factors favor this process, including tau phosphorylation and zinc ions.[43][44]

Release[edit]

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.[45] On the other hand, tau release depends on neuronal activity. Many factors influence tau release, for example, type of isoforms or MAPT mutations that change the extracellular level of tau.[46] According to Asai and his colleagues, the spreading of tau protein occurs from the 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.[47]

Toxicity[edit]

Tau causes toxic effects through its accumulation inside cells. Many enzymes are involved in toxicity mechanism such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn leads to activate other kinases (GSK-3 and CDK5) that cause disease-associated phosphoepitopes.[48] The degree of toxicity is affected by different factors, such as the degree of microtubule binding.[49][50] Toxicity could also happen by neurofibrillary tangles (NFTs), which leads to cell death and cognitive decline.

Clinical significance[edit]

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.[51] All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments in the 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.[52]

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.[53] Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.[54]

Tau hypothesis of Alzheimer's disease[edit]

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).[55] The stage of the disease determines NFTs' phosphorylation. In AD, at least 19 amino acids are phosphorylated; pre-NFT phosphorylation occurs at serine 119, 202 and 409, while intra-NFT phosphorylation happens at serine 396 and threonine 231.[56] 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.[57] 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. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1 (microtubule associated protein tau 1), 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.[58][52]

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.[59] Hyperphosphorylated tau differs in its sensitivity and its kinase as well as alkaline phosphatase activity[60] and is, along with beta-amyloid, a component of the pathologic lesion seen in Alzheimer disease.[61][62]

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.[63]

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.[64][65][66]

Traumatic brain injury[edit]

Repetitive mild traumatic brain injury (TBI) is a central component of contact sports, especially American football,[67][68] and the concussive force of military blasts.[69] It can lead to chronic traumatic encephalopathy (CTE), a condition characterized by fibrillar tangles of hyperphosphorylated tau.[70] After severe traumatic brain injury, high levels of tau protein in extracellular fluid in the brain are linked to poor outcomes.[71]

Interactions[edit]

Tau protein has been shown to interact with:

See also[edit]

References[edit]

  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. ^ Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (June 1988). "Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau". Proceedings of the National Academy of Sciences of the United States of America. 85 (11): 4051–5. Bibcode:1988PNAS...85.4051G. doi:10.1073/pnas.85.11.4051. PMC 280359. PMID 3131773.
  6. ^ Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (October 1989). "Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease". Neuron. 3 (4): 519–26. doi:10.1016/0896-6273(89)90210-9. PMID 2484340. S2CID 19627629.
  7. ^ Shin RW, Iwaki T, Kitamoto T, Tateishi J (May 1991). "Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues". Laboratory Investigation; A Journal of Technical Methods and Pathology. 64 (5): 693–702. PMID 1903170.
  8. ^ Lei P, Ayton S, Finkelstein DI, Adlard PA, Masters CL, Bush AI (November 2010). "Tau protein: relevance to Parkinson's disease". The International Journal of Biochemistry & Cell Biology. 42 (11): 1775–8. doi:10.1016/j.biocel.2010.07.016. PMID 20678581.
  9. ^ Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (May 1975). "A protein factor essential for microtubule assembly". Proceedings of the National Academy of Sciences of the United States of America. 72 (5): 1858–62. Bibcode:1975PNAS...72.1858W. doi:10.1073/pnas.72.5.1858. PMC 432646. PMID 1057175.
  10. ^ a b c Cleveland DW, Hwo SY, Kirschner MW (October 1977). "Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin". Journal of Molecular Biology. 116 (2): 207–25. doi:10.1016/0022-2836(77)90213-3. PMID 599557.
  11. ^ Cleveland DW, Hwo SY, Kirschner MW (October 1977). "Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly". Journal of Molecular Biology. 116 (2): 227–47. doi:10.1016/0022-2836(77)90214-5. PMID 146092.
  12. ^ a b c d e f Papanikolopoulou K, Roussou IG, Gouzi JY, Samiotaki M, Panayotou G, Turin L, Skoulakis EM (October 2019). "Drosophila Tau Negatively Regulates Translation and Olfactory Long-Term Memory, But Facilitates Footshock Habituation and Cytoskeletal Homeostasis". The Journal of Neuroscience. 39 (42): 8315–8329. doi:10.1523/JNEUROSCI.0391-19.2019. PMC 6794924. PMID 31488613.
  13. ^ a b Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, et al. (June 1994). "Altered microtubule organization in small-calibre axons of mice lacking tau protein". Nature. 369 (6480): 488–91. Bibcode:1994Natur.369..488H. doi:10.1038/369488a0. PMID 8202139. S2CID 4322543.
  14. ^ Wang JZ, Liu F (June 2008). "Microtubule-associated protein tau in development, degeneration and protection of neurons". Progress in Neurobiology. 85 (2): 148–75. doi:10.1016/j.pneurobio.2008.03.002. PMID 18448228. S2CID 32708424.
  15. ^ Ke YD, Suchowerska AK, van der Hoven J, De Silva DM, Wu CW, van Eersel J, et al. (June 2012). "Lessons from tau-deficient mice". International Journal of Alzheimer's Disease. 2012 (873270): 873270. doi:10.1155/2012/873270. PMC 3375147. PMID 22720190.
  16. ^ Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J, et al. (August 2010). "Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models". Cell. 142 (3): 387–97. doi:10.1016/j.cell.2010.06.036. PMID 20655099. S2CID 18776289.
  17. ^ Dehmelt L, Halpain S (2004). "The MAP2/Tau family of microtubule-associated proteins". Genome Biology. 6 (1): 204. doi:10.1186/gb-2004-6-1-204. PMC 549057. PMID 15642108.
  18. ^ a b Meier S, Bell M, Lyons DN, Rodriguez-Rivera J, Ingram A, Fontaine SN, et al. (January 2016). "Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis". The Journal of Neuroscience. 36 (3): 1001–7. doi:10.1523/JNEUROSCI.3029-15.2016. PMC 4719006. PMID 26791227.
  19. ^ Koren SA, Hamm MJ, Meier SE, Weiss BE, Nation GK, Chishti EA, et al. (April 2019). "Tau drives translational selectivity by interacting with ribosomal proteins". Acta Neuropathologica. 137 (4): 571–583. doi:10.1007/s00401-019-01970-9. PMC 6426815. PMID 30759285.
  20. ^ Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP (March 2001). "Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice". Journal of Cell Science. 114 (Pt 6): 1179–87. PMID 11228161.
  21. ^ Fujio K, Sato M, Uemura T, Sato T, Sato-Harada R, Harada A (July 2007). "14-3-3 proteins and protein phosphatases are not reduced in tau-deficient mice". NeuroReport. 18 (10): 1049–52. doi:10.1097/WNR.0b013e32818b2a0b. PMID 17558294. S2CID 25235996.
  22. ^ a b Ikegami S, Harada A, Hirokawa N (February 2000). "Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice". Neuroscience Letters. 279 (3): 129–32. doi:10.1016/s0304-3940(99)00964-7. PMID 10688046. S2CID 31204860.
  23. ^ Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. (May 2007). "Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model". Science. 316 (5825): 750–4. Bibcode:2007Sci...316..750R. doi:10.1126/science.1141736. PMID 17478722. S2CID 32771613.
  24. ^ Dawson HN, Cantillana V, Jansen M, Wang H, Vitek MP, Wilcock DM, et al. (August 2010). "Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease". Neuroscience. 169 (1): 516–31. doi:10.1016/j.neuroscience.2010.04.037. PMC 2900546. PMID 20434528.
  25. ^ Cantero JL, Hita-Yañez E, Moreno-Lopez B, Portillo F, Rubio A, Avila J (August 2010). "Tau protein role in sleep-wake cycle". Journal of Alzheimer's Disease. 21 (2): 411–21. doi:10.3233/JAD-2010-100285. PMID 20555133.
  26. ^ Wang JZ, Liu F (June 2008). "Microtubule-associated protein tau in development, degeneration and protection of neurons". Progress in Neurobiology. 85 (2): 148–75. doi:10.1016/j.pneurobio.2008.03.002. PMID 18448228. S2CID 32708424.
  27. ^ Sotiropoulos I, Galas MC, Silva JM, Skoulakis E, Wegmann S, Maina MB, et al. (November 2017). "Atypical, non-standard functions of the microtubule associated Tau protein". Acta Neuropathologica Communications. 5 (1): 91. doi:10.1186/s40478-017-0489-6. PMC 5707803. PMID 29187252.
  28. ^ Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA (December 1986). "Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2". Brain Research. 387 (3): 271–80. doi:10.1016/0169-328x(86)90033-1. PMID 3103857.
  29. ^ Sergeant N, Delacourte A, Buée L (January 2005). "Tau protein as a differential biomarker of tauopathies". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1739 (2–3): 179–97. doi:10.1016/j.bbadis.2004.06.020. PMID 15615637.
  30. ^ Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, et al. (September 2006). "Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability". Nature Genetics. 38 (9): 1032–7. doi:10.1038/ng1858. PMID 16906163. S2CID 38047848.
  31. ^ Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, et al. (September 2008). "Evolutionary toggling of the MAPT 17q21.31 inversion region". Nature Genetics. 40 (9): 1076–83. doi:10.1038/ng.193. PMC 2684794. PMID 19165922.
  32. ^ Almos PZ, Horváth S, Czibula A, Raskó I, Sipos B, Bihari P, et al. (November 2008). "H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population". Heredity. 101 (5): 416–9. doi:10.1038/hdy.2008.70. PMID 18648385.
  33. ^ Hardy J, Pittman A, Myers A, Gwinn-Hardy K, Fung HC, de Silva R, et al. (August 2005). "Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens". Biochemical Society Transactions. 33 (Pt 4): 582–5. doi:10.1042/BST0330582. PMID 16042549.
  34. ^ Billingsley ML, Kincaid RL (May 1997). "Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration". The Biochemical Journal. 323 ( Pt 3) (3): 577–91. doi:10.1042/bj3230577. PMC 1218358. PMID 9169588.
  35. ^ Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, et al. (March 2001). "Phosphorylation of tau is regulated by PKN". The Journal of Biological Chemistry. 276 (13): 10025–31. doi:10.1074/jbc.M007427200. PMID 11104762.
  36. ^ Kanemaru K, Takio K, Miura R, Titani K, Ihara Y (May 1992). "Fetal-type phosphorylation of the tau in paired helical filaments". Journal of Neurochemistry. 58 (5): 1667–75. doi:10.1111/j.1471-4159.1992.tb10039.x. PMID 1560225. S2CID 94265621.
  37. ^ Mawal-Dewan M, Henley J, Van de Voorde A, Trojanowski JQ, Lee VM (December 1994). "The phosphorylation state of tau in the developing rat brain is regulated by phosphoprotein phosphatases". The Journal of Biological Chemistry. 269 (49): 30981–7. PMID 7983034.
  38. ^ Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O'Connor M, Trojanowski JQ, Lee VM (October 1994). "Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau". Neuron. 13 (4): 989–1002. doi:10.1016/0896-6273(94)90264-X. PMID 7946342. S2CID 40592137.
  39. ^ Liu, Fei; Iqbal, Khalid; Grundke-Iqbal, Inge; Hart, Gerald W.; Gong, Cheng-Xin (2004-07-20). "O-GlcNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America. 101 (29): 10804–10809. Bibcode:2004PNAS..10110804L. doi:10.1073/pnas.0400348101. ISSN 0027-8424. PMC 490015. PMID 15249677.
  40. ^ Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (January 1997). "Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau". Proceedings of the National Academy of Sciences of the United States of America. 94 (1): 298–303. Bibcode:1997PNAS...94..298A. doi:10.1073/pnas.94.1.298. PMC 19321. PMID 8990203.
  41. ^ Frost B, Jacks RL, Diamond MI (May 2009). "Propagation of tau misfolding from the outside to the inside of a cell". The Journal of Biological Chemistry. 284 (19): 12845–52. doi:10.1074/jbc.M808759200. PMC 2676015. PMID 19282288.
  42. ^ Calafate S, Buist A, Miskiewicz K, Vijayan V, Daneels G, de Strooper B, et al. (May 2015). "Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation" (PDF). Cell Reports. 11 (8): 1176–83. doi:10.1016/j.celrep.2015.04.043. PMID 25981034.
  43. ^ Roman AY, Devred F, Byrne D, La Rocca R, Ninkina NN, Peyrot V, Tsvetkov PO (February 2019). "Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau". Journal of Molecular Biology. 431 (4): 687–695. doi:10.1016/j.jmb.2018.12.008. PMID 30580037.
  44. ^ Fichou Y, Al-Hilaly YK, Devred F, Smet-Nocca C, Tsvetkov PO, Verelst J, et al. (March 2019). "The elusive tau molecular structures: can we translate the recent breakthroughs into new targets for intervention?". Acta Neuropathologica Communications. 7 (1): 31. doi:10.1186/s40478-019-0682-x. PMC 6397507. PMID 30823892.
  45. ^ Goedert M, Eisenberg DS, Crowther RA (July 2017). "Propagation of Tau Aggregates and Neurodegeneration". Annual Review of Neuroscience. 40 (1): 189–210. doi:10.1146/annurev-neuro-072116-031153. PMID 28772101.
  46. ^ Yamada K (2017). "Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology". Frontiers in Neuroscience. 11: 667. doi:10.3389/fnins.2017.00667. PMC 5712583. PMID 29238289.
  47. ^ Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. (November 2015). "Depletion of microglia and inhibition of exosome synthesis halt tau propagation". Nature Neuroscience. 18 (11): 1584–93. doi:10.1038/nn.4132. PMC 4694577. PMID 26436904.
  48. ^ Nishimura I, Yang Y, Lu B (March 2004). "PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila". Cell. 116 (5): 671–82. doi:10.1016/S0092-8674(04)00170-9. PMID 15006350. S2CID 18896805.
  49. ^ Chatterjee S, Sang TK, Lawless GM, Jackson GR (January 2009). "Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model". Human Molecular Genetics. 18 (1): 164–77. doi:10.1093/hmg/ddn326. PMC 2644648. PMID 18930955.
  50. ^ Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, et al. (April 2005). "Tau phosphorylation in Alzheimer's disease: pathogen or protector?". Trends in Molecular Medicine. 11 (4): 164–9. doi:10.1016/j.molmed.2005.02.008. hdl:10316/4769. PMID 15823754.
  51. ^ Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K (June 2001). "Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments". Proceedings of the National Academy of Sciences of the United States of America. 98 (12): 6923–8. Bibcode:2001PNAS...98.6923A. doi:10.1073/pnas.121119298. PMC 34454. PMID 11381127.
  52. ^ a b “Alzheimer's Brain Tangles.” Alzheimer's Association, www.alz.org/braintour/tangles.asp.
  53. ^ Köglsberger S, Cordero-Maldonado ML, Antony P, Forster JI, Garcia P, Buttini M, et al. (December 2017). "Gender-Specific Expression of Ubiquitin-Specific Peptidase 9 Modulates Tau Expression and Phosphorylation: Possible Implications for Tauopathies". Molecular Neurobiology. 54 (10): 7979–7993. doi:10.1007/s12035-016-0299-z. PMC 5684262. PMID 27878758.
  54. ^ Hall GF, Patuto BA (July 2012). "Is tau ready for admission to the prion club?". Prion. 6 (3): 223–33. doi:10.4161/pri.19912. PMC 3399531. PMID 22561167.
  55. ^ Mohandas E, Rajmohan V, Raghunath B (January 2009). "Neurobiology of Alzheimer's disease". Indian Journal of Psychiatry. 51 (1): 55–61. doi:10.4103/0019-5545.44908. PMC 2738403. PMID 19742193.
  56. ^ Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (January 2002). "Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease". Acta Neuropathologica. 103 (1): 26–35. doi:10.1007/s004010100423. PMID 11837744. S2CID 6799990.
  57. ^ van Slegtenhorst M, Lewis J, Hutton M (July 2000). "The molecular genetics of the tauopathies". Experimental Gerontology. 35 (4): 461–71. doi:10.1016/S0531-5565(00)00114-5. PMID 10959034. S2CID 38730940.
  58. ^ Mudher A, Lovestone S (January 2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends in Neurosciences. 25 (1): 22–6. doi:10.1016/s0166-2236(00)02031-2. PMID 11801334. S2CID 37380445.
  59. ^ Pradeepkiran JA, Reddy PH (March 2019). "Structure Based Design and Molecular Docking Studies for Phosphorylated Tau Inhibitors in Alzheimer's Disease". Cells. 8 (3): 260. doi:10.3390/cells8030260. PMC 6468864. PMID 30893872.
  60. ^ Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hübschmann S, et al. (December 2014). "Oligomer formation of tau protein hyperphosphorylated in cells". The Journal of Biological Chemistry. 289 (49): 34389–407. doi:10.1074/jbc.M114.611368. PMC 4256367. PMID 25339173.
  61. ^ Shin RW, Bramblett GT, Lee VM, Trojanowski JQ (July 1993). "Alzheimer disease A68 proteins injected into rat brain induce codeposits of beta-amyloid, ubiquitin, and alpha 1-antichymotrypsin". Proceedings of the National Academy of Sciences of the United States of America. 90 (14): 6825–8. Bibcode:1993PNAS...90.6825S. doi:10.1073/pnas.90.14.6825. PMC 47025. PMID 8393578.
  62. ^ Vincent IJ, Davies P (October 1990). "Phosphorylation characteristics of the A68 protein in Alzheimer's disease". Brain Research. 531 (1–2): 127–35. doi:10.1016/0006-8993(90)90765-4. PMID 2126970. S2CID 23900723.
  63. ^ "A68", The Free Dictionary, retrieved 2020-01-27
  64. ^ Belluck, Pam (2020-07-28). "'Amazing, Isn't It?' Long-Sought Blood Test for Alzheimer's in Reach". The New York Times. ISSN 0362-4331. Retrieved 2020-07-29.
  65. ^ Barthélemy, Nicolas R.; Horie, Kanta; Sato, Chihiro; Bateman, Randall J. (2020-11-02). "Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease". Journal of Experimental Medicine. 217 (11). doi:10.1084/jem.20200861. ISSN 0022-1007. PMID 32725127.
  66. ^ Palmqvist, Sebastian; Janelidze, Shorena; Quiroz, Yakeel T.; Zetterberg, Henrik; Lopera, Francisco; Stomrud, Erik; Su, Yi; Chen, Yinghua; Serrano, Geidy E.; Leuzy, Antoine; Mattsson-Carlgren, Niklas (2020-07-28). "Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders". JAMA. 324 (8): 772–781. doi:10.1001/jama.2020.12134. PMC 7388060. PMID 32722745.
  67. ^ "Brain Trauma". NOVA. PBS Online by WGBH.
  68. ^ Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH (July 2005). "Chronic traumatic encephalopathy in a National Football League player". Neurosurgery. 57 (1): 128–34, discussion 128–34. doi:10.1227/01.NEU.0000163407.92769.ED. PMID 15987548. S2CID 196391183.
  69. ^ Goldstein LE, Fisher AM, Tagge CA, Zhang XL, Velisek L, Sullivan JA, et al. (May 2012). "Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model". Science Translational Medicine. 4 (134): 134ra60. doi:10.1126/scitranslmed.3003716. PMC 3739428. PMID 22593173.
  70. ^ McKee AC, Stern RA, Nowinski CJ, Stein TD, Alvarez VE, Daneshvar DH, et al. (January 2013). "The spectrum of disease in chronic traumatic encephalopathy". Brain. 136 (Pt 1): 43–64. doi:10.1093/brain/aws307. PMC 3624697. PMID 23208308.
  71. ^ Magnoni S, Esparza TJ, Conte V, Carbonara M, Carrabba G, Holtzman DM, et al. (April 2012) [first published online November 24, 2011]. "Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury". Brain. 135 (Pt 4): 1268–80. doi:10.1093/brain/awr286. PMC 3326246. PMID 22116192. Lay summaryWashington University in St. Louis.
  72. ^ Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R (September 1999). "alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356". The Journal of Biological Chemistry. 274 (36): 25481–9. doi:10.1074/jbc.274.36.25481. PMID 10464279.
  73. ^ Giasson BI, Lee VM, Trojanowski JQ (2003). "Interactions of amyloidogenic proteins". Neuromolecular Medicine. 4 (1–2): 49–58. doi:10.1385/NMM:4:1-2:49. PMID 14528052. S2CID 9086733.
  74. ^ Klein C, Kramer EM, Cardine AM, Schraven B, Brandt R, Trotter J (February 2002). "Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau". The Journal of Neuroscience. 22 (3): 698–707. doi:10.1523/JNEUROSCI.22-03-00698.2002. PMC 6758498. PMID 11826099.
  75. ^ Yu WH, Fraser PE (April 2001). "S100beta interaction with tau is promoted by zinc and inhibited by hyperphosphorylation in Alzheimer's disease". The Journal of Neuroscience. 21 (7): 2240–6. doi:10.1523/JNEUROSCI.21-07-02240.2001. PMC 6762409. PMID 11264299.
  76. ^ Baudier J, Cole RD (April 1988). "Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II". The Journal of Biological Chemistry. 263 (12): 5876–83. PMID 2833519.
  77. ^ Hashiguchi M, Sobue K, Paudel HK (August 2000). "14-3-3zeta is an effector of tau protein phosphorylation". The Journal of Biological Chemistry. 275 (33): 25247–54. doi:10.1074/jbc.M003738200. PMID 10840038.

Further reading[edit]

External links[edit]