MAPT

This gene encodes the microtubule-associated protein tau (MAPT) whose transcript undergoes complex, regulated alternative splicing, giving rise to several mRNA species. MAPT transcripts are differentially expressed in the nervous system, depending on stage of neuronal maturation and neuron type. MAPT gene mutations have been associated with several neurodegenerative disorders such as Alzheimer's disease, Pick's disease, frontotemporal dementia, cortico-basal degeneration and progressive supranuclear palsy. [provided by RefSeq, Jul 2008]

Microtubule Associated Protein Tau

Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity (PubMed:21985311).
The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both (PubMed:21985311, PubMed:32961270).
Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.

Activation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Amyloid fibril formationManual Assertion Based On ExperimentIMP:CAFA
Astrocyte activationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Axon developmentManual Assertion Based On ExperimentTAS:ARUK-UCL
Axonal transportManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Axonal transport of mitochondrionManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Cell-cell signaling1 PublicationNAS:ARUK-UCL
Cellular response to brain-derived neurotrophic factor stimulusManual Assertion Based On ExperimentTAS:ARUK-UCL
Cellular response to heatManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Cellular response to nerve growth factor stimulusManual Assertion Based On ExperimentTAS:ARUK-UCL
Cellular response to reactive oxygen speciesManual Assertion Based On ExperimentTAS:ARUK-UCL
Central nervous system neuron developmentManual Assertion Based On ExperimentTAS:ARUK-UCL
Cytoplasmic microtubule organizationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Generation of neurons1 PublicationNAS:UniProtKB
Internal protein amino acid acetylationManual Assertion Based On ExperimentTAS:ARUK-UCL
Intracellular distribution of mitochondriaManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Learning or memoryIMP:ARUK-UCL
MemoryManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Microglial cell activationManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Microtubule cytoskeleton organizationManual Assertion Based On ExperimentIDA:UniProtKB
Microtubule polymerizationManual Assertion Based On ExperimentIDA:ARUK-UCL
Negative regulation of establishment of protein localization to mitochondrionManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of gene expressionManual Assertion Based On ExperimentIMP:ARUK-UCL
Negative regulation of kinase activityManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of mitochondrial fissionManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of mitochondrial membrane potentialManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Negative regulation of tubulin deacetylationManual Assertion Based On ExperimentIGI:ARUK-UCL
Neurofibrillary tangle assembly1 PublicationNAS:ParkinsonsUK-UCL
Neuron projection developmentManual Assertion Based On ExperimentIBA:GO_Central
Plus-end-directed organelle transport along microtubuleManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Positive regulation of axon extensionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of diacylglycerol kinase activityISS:ParkinsonsUK-UCL
Positive regulation of microtubule polymerizationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of neuron deathManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of protein localizationManual Assertion Based On ExperimentIMP:CAFA
Positive regulation of protein localization to synapseManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of superoxide anion generationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Protein homooligomerizationIMP:ARUK-UCL
Protein polymerizationManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of autophagyManual Assertion Based On ExperimentIGI:MGI
Regulation of calcium-mediated signalingManual Assertion Based On ExperimentIDA:ARUK-UCL
Regulation of cellular response to heatManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of chromosome organizationManual Assertion Based On ExperimentTAS:ARUK-UCL
Regulation of long-term synaptic depressionManual Assertion Based On ExperimentTAS:ARUK-UCL
Regulation of microtubule cytoskeleton organizationManual Assertion Based On ExperimentIMP:CAFA
Regulation of microtubule polymerizationManual Assertion Based On ExperimentTAS:ARUK-UCL
Regulation of microtubule polymerization or depolymerizationManual Assertion Based On ExperimentIMP:CAFA
Regulation of mitochondrial fission1 PublicationIC:ParkinsonsUK-UCL
Regulation of response to DNA damage stimulusManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Regulation of synaptic plasticityManual Assertion Based On ExperimentTAS:ARUK-UCL
Response to lead ionISS:ARUK-UCL
rRNA metabolic processManual Assertion Based On ExperimentTAS:ARUK-UCL
Stress granule assemblyManual Assertion Based On ExperimentTAS:ARUK-UCL
Supramolecular fiber organizationManual Assertion Based On ExperimentIDA:CAFA
Synapse assemblyIMP:ARUK-UCL
Synapse organizationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL

Cytoplasm, cytosol
Cell membrane 1 Publication; Peripheral membrane protein
Cytoplasm, cytoskeleton
Cell projection, axon
Cell projection, dendrite
Secreted
Mostly found in the axons of neurons, in the cytosol and in association with plasma membrane components (PubMed:10747907).
Can be secreted; the secretion is dependent on protein unfolding and facilitated by the cargo receptor TMED10; it results in protein translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) followed by vesicle entry and secretion (PubMed:32272059).

In Alzheimer disease, the neuronal cytoskeleton in the brain is progressively disrupted and replaced by tangles of paired helical filaments (PHF) and straight filaments, mainly composed of hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation is greatly reduced in Alzheimer disease brain cerebral cortex leading to an increase in TAU/MAPT phosphorylations.
Frontotemporal dementia (FTD):
A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.
Pick disease of the brain (PIDB):
A rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration.
Defects in MAPT are a cause of corticobasal degeneration (CBD). It is marked by extrapyramidal signs and apraxia and can be associated with memory loss. Neuropathologic features may overlap Alzheimer disease, progressive supranuclear palsy, and Parkinson disease
Progressive supranuclear palsy 1 (PSNP1):
Characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613.
Parkinson-dementia syndrome (PARDE):
A syndrome characterized by parkinsonism, tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei.

Phosphorylation at serine and threonine residues in S-P or T-P motifs by proline-directed protein kinases (PDPK1, CDK1, CDK5, GSK3, MAPK) (only 2-3 sites per protein in interphase, seven-fold increase in mitosis, and in the form associated with paired helical filaments (PHF-tau)), and at serine residues in K-X-G-S motifs by MAP/microtubule affinity-regulating kinase (MARK1, MARK2, MARK3 or MARK4), causing detachment from microtubules, and their disassembly (PubMed:7706316, PubMed:23666762).
Phosphorylation decreases with age. Phosphorylation within tau/MAP's repeat domain or in flanking regions seems to reduce tau/MAP's interaction with, respectively, microtubules or plasma membrane components (PubMed:7706316).
Phosphorylation on Ser-610, Ser-622, Ser-641 and Ser-673 in several isoforms during mitosis. Phosphorylation at Ser-548 by GSK3B reduces ability to bind and stabilize microtubules. Phosphorylation at Ser-579 by BRSK1 and BRSK2 in neurons affects ability to bind microtubules and plays a role in neuron polarization. Phosphorylated at Ser-554, Ser-579, Ser-602, Ser-606 and Ser-669 by PHK. Phosphorylation at Ser-214 by SGK1 mediates microtubule depolymerization and neurite formation in hippocampal neurons. There is a reciprocal down-regulation of phosphorylation and O-GlcNAcylation. Phosphorylation on Ser-717 completely abolishes the O-GlcNAcylation on this site, while phosphorylation on Ser-713 and Ser-721 reduces glycosylation by a factor of 2 and 4 respectively. Phosphorylation on Ser-721 is reduced by about 41.5% by GlcNAcylation on Ser-717. Dephosphorylated at several serine and threonine residues by the serine/threonine phosphatase PPP5C.
Polyubiquitinated. Requires functional TRAF6 and may provoke SQSTM1-dependent degradation by the proteasome (By similarity).
PHF-tau can be modified by three different forms of polyubiquitination. 'Lys-48'-linked polyubiquitination is the major form, 'Lys-6'-linked and 'Lys-11'-linked polyubiquitination also occur.
O-glycosylated. O-GlcNAcylation content is around 8.2%. There is reciprocal down-regulation of phosphorylation and O-GlcNAcylation. Phosphorylation on Ser-717 completely abolishes the O-GlcNAcylation on this site, while phosphorylation on Ser-713 and Ser-721 reduces O-GlcNAcylation by a factor of 2 and 4 respectively. O-GlcNAcylation on Ser-717 decreases the phosphorylation on Ser-721 by about 41.5%.
Glycation of PHF-tau, but not normal brain TAU/MAPT. Glycation is a non-enzymatic post-translational modification that involves a covalent linkage between a sugar and an amino group of a protein molecule forming ketoamine. Subsequent oxidation, fragmentation and/or cross-linking of ketoamine leads to the production of advanced glycation endproducts (AGES). Glycation may play a role in stabilizing PHF aggregation leading to tangle formation in AD.