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FLASH GENE
Symbol MAPT contributors: mct/pgu - updated : 26-01-2013
HGNC name microtubule-associated protein tau
HGNC id 6893
Corresponding disease
DEL17Q21 chromosome 17q21.31 microdeletion syndrome
DUP17Q21 chromosome 17q21 microduplication syndrome
FTDP17 frontotemporal dementia with parkinsonism
PSRP progressive supranuclear palsy
Location 17q21.31      Physical location : 762.282 - 44.105.697
Synonym name
  • G protein beta1/gamma2 subunit-interacting factor 1
  • neurofibrillary tangle protein
  • paired helical filament-tau
  • microtubule-associated protein tau-like
  • microtubule-associated protein tau, isoform 4
    • Synonym symbol(s) MTBT1, TAU, MSTD, PPND, DDPAC, FLJ31424, FTDP-17, MAPTL, MTBT1, MTBT2, MGC138549
    DNA
    TYPE functioning gene
    STRUCTURE 134.00 kb     15 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    text structure
  • exons numbered from 1 to 14, with a duplication exon 4 (4/4a), two N terminal alternatively spliced exons
  • Saitohin (STH) gene is located in the intron between exons 9 and 10 of the human MAPT gene
    • MAPPING cloned Y linked N status confirmed
    Map cen - D17S950 - D17S810 - MAPT - D17S920 - D17S791 - qter
    Physical map
    FLJ22955 17q21.31 hypothetical protein FLJ22955 NMT1 17q21.32 N-myristoyltransferase 1 PLCD3 17q21 phospholipase C, delta 3 ACBD4 17q21.31 acyl-Coenzyme A binding domain containing 4 HIS1 17q21.1 acyl-Coenzyme A binding domain containing 4 FLJ32384 17q21.31 hypothetical protein MGC39389 FMNL1 17q21 formin-like 1 FLJ25414 17q21.31 hypothetical protein FLJ25414 MAP3K14 17q21 mitogen-activated protein kinase kinase kinase 14 LOC388390 17 LOC388390 LOC201176 17q21.31 similar to Rho GTPase activating protein 12 LOC201175 17q21.31 hypothetical protein LOC201175 KIAA0356 17q21.1-q23.2 hypothetical protein LOC201175 FLJ10120 17q21.31 hypothetical protein FLJ10120 LOC388391 17 similar to KIAA0563 protein LOC339193 17q21.31 similar to dead end homolog 1; dead end protein FLJ25168 17q21.31 hypothetical protein FLJ25168 CRHR1 17q12-q22 corticotropin releasing hormone receptor 1 IMP5 17q21.31 intramembrane protease 5 MAPT 17q21.11 microtubule-associated protein tau DKFZP727C091 LOC284054 17q21.32 similar to C-jun-amino-terminal kinase interacting protein 1 (JNK-interacting protein 1) (JIP-1) (JNK MAP kinase scaffold protein 1) (Islet-brain-1) (IB-1) (Mitogen-activated protein kinase 8-interacting protein 1) LOC124981 17q21.32 similar to dead end homolog 1; dead end protein LOC388392 17 similar to FALZ protein LOC201173 17q21.32 similar to KIAA0563 protein LOC51326 17q21.32 ARF protein NSF 17q21-q22 N-ethylmaleimide-sensitive factor
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    14 - 6762 78.88 758 nervous system, mainly in axons 2008 18940799
  • full length
  • also called PNS-tau
  • 4-repeat Tau
    • 12 splicing 5811 45.72 441 nervous system, mainly in axons 2008 18940799
  • exons 2+, 3+, 10+
  • lacking 4a & 6
  • 4-repeat Tau
    • 10 splicing 5637 39.87 383 nervous system, mainly in axons 2008 18940799
  • exon 10+
  • lacking 2, 3, 4a & 6
  • 4-repeat Tau
  • encodes the second microtubule-binding repeat, and is regulated by alternative splicing
    • 9 splicing 5464 36.63 352 nervous system, mainly in axons 2008 18940799
  • lacking 2, 3, 4a, 6 & 10
  • 3-repeat Tau
    • 15 - 6816 - 776 nervous system, mainly in axons 2008 18940799
    11 - 5724 - 412 nervous system, mainly in axons 2008 18940799
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
    Endocrinepancreas   moderately
    Nervousbrain   highly
     nerve   highly
    Reproductivemale systemtestis  moderately
    Respiratorylung   moderately
    Urinarykidney   moderately
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    Nervousperipherous   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousastrocyte
    Nervousneuron
    Nervousoligodendrocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four conserved imperfect 18 AA repeats (microtubule binding motifs)
  • a proline rich region
  • another microtubule binding motif alternatively spliced in the C terminal region (exon 10)
  • fibril-forming motifs with a key role in the fibrillization of MAPT protein and determinants of amyloidogenic proteins tending to misfold, thereby causing the initiation and development of neurodegenerative diseases
    • HOMOLOGY
    interspecies ortholog to MAPT, Pan troglodytes
    ortholog to Mapt, Rattus norvegicus
    ortholog to Mapt, Mus musculus
    Homologene
    FAMILY
    CATEGORY structural protein , transport
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule
    basic FUNCTION
  • essential for microtubule assembly
  • necessary for the establishment of neuronal cell polarity, axonal outgrowth, and axonal transport and the maintenance of axonal morphology regulating the transport of vesicles or organelles along microtubules and maintenance of neuron polarity
  • toxicity of intracellular tau to neuronal cells
  • may regulate the subcellular localization and function of calmodulin in neurons
  • strongly implicated as a dosage-sensitive gene in this locus involved in intellectual disability
  • acts as an independent genetic risk factor in pathologically proven Parkinson disease
  • may alter the glucocorticoids -mediated regulation of PKA activity and CREB phosphorylation
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • primary constituent of paired helical filaments
    • INTERACTION
    DNA
    RNA
    small molecule
  • phosphorylated by Akt/PKB kinase
    • protein
  • SFRS10 (target gene for the alternative splicing regulator SFRS10)
  • Rb binding protein Che-1 (AATF)
  • apolipoprotein E3 (ApoE3)
  • calmodulin 1 (phosphorylase kinase, delta) (CALM1)
  • Fyn kinase (FYN)
  • prolyl isomerase Pin1
  • Presenilin 1 (PSEN1)
  • S100 calcium binding protein B (S100B)
  • alpha-synuclein (SNCA)
  • spectrin (SPTB)
  • alpha and beta tubulin
  • ubiquitin
  • 14-3-3zeta protein
  • beta PP peptide
  • BCL2-associated athanogene 1 (BAG-1)
  • Amyloid-beta protein (Abeta)
  • interacting with CALM1 (the lack of MAPT in neurons changes the subcellular localization of CALM1 and that it correlates with a change in the expression of calbindin)
  • SRSF4 binds to the proximal downstream intron of MAPT exon 10 at the FTDP-17 hotspot region and interacts with RBMX and PCBP2 (increased exon 10 inclusion in FTDP mutants may arise from weakened SRSF4 binding)
  • GSK3B activity regulates mitochondrial axonal trafficking largely in a MAPT-dependent manner
  • MAPT mRNA is a physiological splicing target of FUS
  • SRSF6 promoted MAPT exon 10 inclusion, and the promotion of MAPT exon 10 inclusion by SRSF6 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization
  • interaction of endogenous MAPT protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent MAPT phosphorylation
  • NUB1 interacted with both MAPT and GSK3B to disrupt their interaction, and abolished recruitment of GSK3B to MAPT inclusions
    • cell & other
    REGULATION
    Phosphorylated by CDC37 that is able to regulate phosphorylation of MAPT and ultimately its stability
    Other phosphorylated by CDK5 and other kinases with decrease of affinity for microtubules
    caspase cleavage of tau may be a molecular mechanism through wihch lysosomal dysfunction and neurodegeneration are causally linked in Alzeihmer's disease
    tau phosphorylation can regulate its association with motor machinery suggesting that signaling deregulation events can lead to tau mislocalization (
    regulated by CDC37 in two ways: by directly stabilizing it via HSP90 and by regulating the stability of distinct MAPT kinases
    ASSOCIATED DISORDERS
    corresponding disease(s) FTDP17 , PSRP , DEL17Q21 , DUP17Q21
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in extraskeletal myxoid chondrosarcoma and chordoma
    constitutional       loss of function
    forming tangles of paired helical filaments (PHF) consisting of hyperphosphorylated tau protein in Alzheimer disease
    constitutional   insertion    
    inclusion of exon 6c decreases in DM1 (myotonic dystrophy 1) brains compared to control brains whereas inclusion of 6d increases
    constitutional       gain of function
    and KLC1 axonal transport defects can initiate neurodegeneration and/or exacerbate human tau-dependent disease pathways in AD and other neurodegenerative tauopathies
    constitutional     --other  
    splicing misregulation of adult-specific exon 10, which codes for a microtubule binding domain, results in expression of abnormal ratios of tau isoforms, leading to FTDP17
    constitutional     --other  
    loss of axonal mitochondria may play an important role in tau phosphorylation and toxicity in the pathogenesis of AD
    Susceptibility
  • to progressive supranuclear palsy and to corticobasal degeneration
  • to Parkinson disease
  • to amyotrophic lateral sclerosis-parkinsonsim/dementia complex of Guam
    • Variant & Polymorphism SNP , other
  • over-representation of the soluble four repeats tau isoforms which may need a genetic defect in tau and a mitochondrial defect either genetic or toxic leading to tau aggregation
  • SNP H1 preferentially associated with Parkinson disease and H1C with Alzheimer disease
  • SNP 14 and 21 increasing the risk of progressive supranuclear palsy and corticobasal degeneration
  • genotypes at SNP9 interact with SNP6 genotypes to increase risk of amyotrophic lateral sclerosis-parkinsonsim/dementia complex of Guam
  • H1 haplotype increased in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD)
  • H2 haplotype has been found to be related to familial FTD
    • ; H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies
    Candidate gene
    Marker
  • salivary MAPT species could be ideal biomarkers for AD diagnosis, especially at early stages of the disease or even screening asymptomatic subjects
    • Therapy target
    ANIMAL & CELL MODELS
  • mice overexpress the 4R human tau isoform develop axonal degeneration in brain and spinal cord
  • mice expressing mutant (P301L) tau protein exhibit neurofibrillary tangles amyotrophy and progressive motor disturbance
  • double mutant (tau/APP (beta-amyloid precursor protein)) mice develop Abeta deposits and exhibit neurofibrillary tangle pathology enhanced in the limbic system and olfactory cortex
  • mice expressing a repressible human tau variant developed progressive age-related neurofibrillary tangles, neuronal loss, and behavioral impairments