Friday 17 October 2003
tau protein, TAU
Definition: Tau or MAPT is a microtubule-associated protein (MAPs) expressed in neurons that stabilizes microtubules in the axon. Six isoforms, containing either three or four microtubule-binding domains (3R or 4R tau), are expressed in the adult human brain.
The microtubule-associated proteins (MAPs) coassemble with tubulin (MIM.602529) into microtubules in vitro. Microtubule-associated protein tau (TAU) appears to be enriched in axons.
The tau protein is encoded by a single gene (MAPT) located on chromosome 17, although it is alternatively spliced to yield six major protein isoforms in the adult human brain.
The neurofibrillary lesions contain aggregates of the microtubule (MT)-associated protein tau. Under physiological conditions tau is mainly localized to the axon for stabilization of MTs.
In tauopathies such as progressive supranuclear palsy or corticobasal degeneration, tau also forms aggregates in non-neuronal cells. Tau is a phosphoprotein owing to its high numbers of serine and threonine residues, and is therefore a substrate of many kinases.
Under pathological conditions, tau is hyperphosphorylated, which means that it is phosphorylated to a higher degree at physiological sites, as well as at additional ’pathological’ sites (see figure, bottom).
Hypophosphorylated tau dissociates from MTs, causing them to depolymerize, while tau is deposited in aggregates such as NFTs. There is increasing evidence that at early stages of the disease toxicity is exerted by soluble and lower order A and tau species rather than by A plaques and NFTs.
The gene encoding tau, consisting of at least 16 exons, is located on chromosome 17.
The adult brain expresses six isoforms of tau, which differ by the presence of three or four repeats of 31 or 33 amino acids in the C-terminal portion, and none, one or two inserts in the N-terminal region.
The three or four tandem repeats contain domains that are important for microtubule binding. Two proline-rich regions, the phosphorylation of which affect the ability of tau to bind to microtubules, flank the microtubule-binding domain.
It has been suggested that the four-repeat forms favor fibril formation, whereas the three-repeat forms do not. A high molecular weight tau protein, containing a region encoded by an extra exon, has been described in the peripheral nervous system.
Exons 2, 3 and 10 can be alternatively spliced. Four imperfect tandem repeats are encoded by exons 9–12; therefore, the alternative splicing of exon 10 yields isoforms with either three or four repeat domains, referred to as 3R and 4R tau, depending if exon 10 is absent or present, respectively. Alternative splicing of exons 2 and 3 yields variants containing zero (0N), one (1N) or two (2N) inserts at the N-terminus, such that six tau isoforms are formed: 3R0N, 3R1N, 3R2N, 4R0N, 4R1N and 4R2N.
In the adult human brain, the proportion of 3R to 4R tau is 1:1, whereas in the adult mouse brain, 4R tau is the only tau isoform present.
Tauopathies can be further classified based on whether tangles are composed of 3R or 4R tau isoforms. For example, in Alzheimer disease, both 3R and 4R tau accumulate in neurofibrillary tangles; other disorders are marked by only 3R tau (e.g. Pick disease) or 4R tau, e.g. corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). In Alzheimer disease, tau pathology is restricted to neurons, but in certain other tauopathies, such as the 4R tauopathies CBD and PSP, tau inclusions are also observed in glia.
Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. In adult
Neuronal morphology and structural integrity are maintained largely by the cytoskeleton, which is partially composed of microtubules. The assembly and stability of microtubules, in turn, are maintained by microtubule-associated proteins. One such microtubule-associated protein, tau protein (TAU), participates in the association–dissociation cycle of microtubules in neurons.
This protein tau is found primarily in the cytosol, but is also associated with the cell membrane, and it is present mainly, but not exclusively, in axons.
The importance of tau as a microtubule-associated protein was first realized during a search for factors that affect microtubule assembly.
Tau stabilizes microtubules by promoting their polymerization and suppressing their dissociation.
The binding of tau to microtubules, in addition to cell membranes, is highly regulated by phosphorylation.
Tau contains four distinct domains, including the microtubule (tubulin)-binding region, which becomes highly phosphorylated in neurodegenerative diseases. Hypophosphorylated tau binds with high affinity to microtubules, whereas hyperphosphorylated tau, similar to that present in AD, shows a low capacity for binding to microtubules.
Tau phosphorylation and regulation of tau functions
In different neurological disorders, known as tauopathies, modifications in the microtubule-associated protein tau could cause neural degeneration in specific regions. These ’tauopathies’ are due to Tau aggregation into fibrillar polymers.
Although these regions are different in the different tauopathies, some common features appear to occur in all of them: abnormal hyperphosphorylation of tau and aberrant tau aggregation. These two features are commented upon in this review.
mutations in familial cases of frontotemporal dementia. The mutations reduce the ability of tau to promote microtubule assembly. The different tau mutations may result in disturbances in the interactions of the protein tau with microtubules, resulting in hyperphosphorylation of tau protein, assembly into filaments, and subsequent cell death.
Tau is a microtubule-associated protein (MAPs).
In its normal state, tau is a soluble protein that promotes microtubule assembly and stabilization. Pathological tau protein, by contrast, exhibits altered solubility properties, forms filamentous structures and is abnormally phosphorylated at certain residues. It has been shown that phosphorylated tau has reduced affinity for microtubules.
The major component of neurofibrillary tangles (NFTs) is the microtubule-associated protein tau (TAU).
However, the identification of mutations in the tau gene in FTDP-17 has determined the pivotal role of tau in neurodegeneration in this disorder and has demonstrated the central role of tau in determining cell death also in other neurodegenerative diseases where its aggregates are present. This role has been confirmed by the presence of cell death in transgenic mice expressing mutated human tau.
MAPT, the gene encoding tau, is not genetically linked to Alzheimer disease, but MAPT mutations cause FTDP-17. The identification of disease-causing mutations in tau establishes that tau dysfunction suffices to cause neurodegeneration.
The lack of genetic association to Alzheimer disease, however, further corroborates the evidence that tau lies downstream of Aβ in the neurodegenerative cascade.
This should not imply that tau pathology is irrelevant or innocuous in the pathogenesis of AD, because neurodegeneration induced by tau dysfunction might have a pivotal role in AD. This evidence further indicates that tau pathology can be triggered by different mechanisms, both dependent on and independent of Aβ.
MAPT germline mutation in
- frontotemporal dementia (MIM.600274)
- frontotemporal dementia with parkinsonism (MIM.600274)
- pallidopontonigral degeneration (PPND) (MIM.168610)
- Pick disease
Tau protein aggregation (Abundant cytoplasmic inclusions consisting of aggregated hyperphosphorylated protein tau) in
- Alzheimer disease
- Pick disease
- frontotemporal dementia (MIM.600274)
- cortico-basal degeneration
- progressive supranuclear palsy
The question of how a mutation in the tau gene leads to neurodegeneration is, as yet, not fully clear. The primary effect of most missense mutations appears to be the reduced ability of tau to interact
with microtubules. This may be comparable to a partial loss of function, resulting in microtubule destabilization and deficits in cellular processes such as axonal transport.
However, mice lacking the tau gene are fully viable, demonstrating that the microtubule- binding of tau is not an essential function. Furthermore, missense tau mutations do not seem to alter axonal transport.
As FTDP-17 is characterized by filamentous accumulations of hyperphosphorylated tau, perhaps a more plausible explanation for
the effect of mutations is that they lead to a “toxic gain of function.”
Decreased binding of mutated tau to microtubules could result in accumulation of “free” tau, which becomes hyperphosphorylated
and assembles into filaments. 3R and 4R tau may bind to different sites on microtubules, giving a possible explanation for the inability of tau
with 4R to take the place of tau with 3R in FTDP-17, leading to tau accumulation and pathology.
The relevance of hyperphosphorylation in tau aggregation
is debated but because mutations in tau do not create additional phosphorylation sites (with the possible exceptions of the K257T and P301S mutations), hyperphosphorylation probably occurs
downstream of the primary effects of the mutation.
However, the R406W missense mutation may indirectly affect tau phosphorylation because in cells transfected with the R406W mutation, tau is less phosphorylated than wild-type tau, and tau with
the P301L or V337M mutations.
Currently, whether hyperphosphorylation is either necessary or sufficient
for filament assembly in vivo is unclear, transgenic mice with hyperphosphorylated tau but no filaments do not show neurodegeneration.
In recent years great progress has been made in understanding the involvement of tau in neurodegeneration. What remains is to determine
the mechanisms that link tau to cell death and why this occurs in specific brain areas in the various tauopathies.
MAPT, through a toxic gain-of-function mechanism, is capable of inducing neuronal death leading to a wide range of degenerative phenotypes that can be grouped under the FTD or Pick complex of degenerative brain disorders. A toxic gain-of-function is also supported by several animal model studies in which overexpression of mutant and wild-type tau causes neurodegeneration.
MAPT mutations in FTD
In 1998, the first mutations in MAPT causing autosomal dominant FTD were identified and 40 different causative MAPT mutations have been reported in 2005.
Nearly all mutations are located in the C-terminus of the protein and include missense, silent and intronic variations in addition to two single codon deletions clustered in or near the microtubule-binding domains.
MAPT disorders are neuropathologically characterized by absence of Aβ deposits but share with AD the invariable presence of different forms of tau aggregates and are therefore called pure tauopathies.
MAPT mutations most typically present with FTD. However, the spectrum of MAPT disease is surprisingly wide and ranges from phenotypes in which FTD is accompanied by severe parkinsonism and motor neuron disease to degenerative disorders that are, as in the case of the MAPT R406W mutation, clinically hardly distinguishable from AD.
Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)
A primary genetic role of MAPT as a susceptibility gene in sporadic pure tauopathies called progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is likely.
PSP and CBD are sporadic disorders with prominent parkinsonism neuropathologically characterized by tau deposits and are part of the FTD complex of disorders.
Interestingly, homozygosity of MAPT polymorphisms that segregate on the extended H1 haplotype are consistently overrepresented in patients with PSP and CBD.
Although the genetic mechanism explaining this well-replicated association remains unresolved, in vitro studies have suggested that the MAPT H1 haplotype might be more efficient at driving MAPT gene expression than the H2 haplotype.
Tau and neurodegeneration
tau hyperphosphorylation and instability of microtubules ?
tau hyperphosphorylation and topographic redistribution ?
tau hyperphosphorylation and NFTs formation ?
Tau and cerebral senescence
tau in neurons
- tau in medullary anterior horn
tau in glial cells
- tau in astrocytes
tau -/- mice
- Mouse models gave evidence that tau is not necessary for normal cell function. A tau-deficient mouse produced by gene targeting is viable and phenotypically similar to tau-containing mice. The only morphological change observed was a reduction in the number and density of axons in parallel fibers from the cerebellum.
- Furthermore, acknowledging that knocking out a gene might lead to compensatory effects, tau-deficient mice develop increased levels of alternative microtubule-associated proteins, such as MAP1A, to compensate for the loss of tau .
tau surexpression and neurotoxicity in mice and drosophila
expression of mutant tau in mice (P301L, R406W)
tau filaments formation in JNPL3 mice
tauopathy in Drosophila: neurodegeneration without NFTs
tau suppression in a neurodegenerative mouse model improves memory function
Tau reduction does not prevent motor deficits in two mouse models of Parkinson’s disease (PlosONE)
the Ras/MEK/ERK pathway of tau phosphorylation
neurofibrillary tangles (NFTs) (toxic or neuroprotective ?)
tau and conformational diseases
tau hyperphosphorylation and tau dysfunction and aggregation
subcellular loclaization of tau (axonal vs somatodendritic)
tau function (tau and dynactin complexe)
tau and retograde axonla transport
tau and neuronal death
tau and autophagy
tau and therapeutics
Adalbert R, Gilley J, Coleman MP. Abeta, tau and ApoE4 in Alzheimer’s disease: the axonal connection. Trends Mol Med. 2007 Apr;13(4):135-42. PMID: 17344096
Dermaut B, Kumar-Singh S, Rademakers R, Theuns J, Cruts M, Van Broeckhoven C. Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum. Trends Genet. 2005 Dec;21(12):664-72. PMID: 16221505
Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med. 2005 Apr;11(4):164-9. PMID: 15823754
Laferla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PMID: 15823755
D’Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):104-15. PMID: 15615630
Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):240-50. PMID: 15615642
Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):198-210. PMID: 15615638
von Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure.
Biochim Biophys Acta. 2005 Jan 3;1739(2-3):158-66. Epub 2004 Nov 12. PMID: 15615635
Hyman BT, Augustinack JC, Ingelsson M. Transcriptional and conformational changes of the tau molecule in Alzheimer’s disease. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):150-7. PMID: 15615634
Gamblin TC. Potential structure/function relationships of predicted secondary structural elements of tau. Biochim Biophys Acta. 2005 Jan 3;1739(2-3):140-9. PMID: 15615633
Yancopoulou D, Spillantini MG. Tau protein in familial and sporadic diseases. Neuromolecular Med. 2003;4(1-2):37-48. PMID: 14528051
Ingram EM, Spillantini MG. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol Med. 2002 Dec;8(12):555-62. PMID: 12470988
Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121-59. PMID: 11520930
Grundke-Iqbal I, Iqbal K. Tau pathology generated by overexpression of tau. Am J Pathol. 1999 Dec;155(6):1781-5. PMID: 10595905