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FLASH GENE

Symbol

MAPT

contributors: mct/pgu - updated : 26-01-2017

HGNC name	microtubule-associated protein tau
HGNC id	6893

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_016835 14 - 6762 NP_058519 78.88 758 nervous system, mainly in axons 2008 18940799 full length also called PNS-tau 4-repeat Tau NM_005910 12 splicing 5811 NP_005901 45.72 441 nervous system, mainly in axons 2008 18940799 exons 2+, 3+, 10+ lacking 4a & 6 4-repeat Tau NM_016834 10 splicing 5637 NP_058518 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 NM_016841 9 splicing 5464 NP_058525 36.63 352 nervous system, mainly in axons 2008 18940799 lacking 2, 3, 4a, 6 & 10 3-repeat Tau NM_001123066 15 - 6816 NP_001116538 - 776 nervous system, mainly in axons 2008 18940799 NM_001123067 11 - 5724 NP_001116539 - 412 nervous system, mainly in axons 2008 18940799

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       moderately Endocrine pancreas       moderately Nervous brain       highly   nerve       highly Reproductive male system testis     moderately Respiratory lung       moderately Urinary kidney       moderately Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous astrocyte Nervous neuron Nervous oligodendrocyte

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
	loss of axonal mitochondria may play an important role in MAPT phosphorylation and toxicity in the pathogenesis of Alzheimer disease

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)
	YWHAZ monomeric form interacts with MAPT and with the HSPB6 protein
	GSK3B activity regulates mitochondrial axonal trafficking largely in a MAPT-dependent manner
	HTRA1 degrades MAPT aggregates and is induced by its substrates
	CDC37 is essential for the stability of TARDBP and can be affected by MAPT accumulation
	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
	ER stress reduced the binding between MAPT and STUB1, ubiquitin E3 ligase for MAPT (STUB1 binds to MAPT and is thought to promote the degradation of MAPT by its ubiquitination through ubiquitin–proteasome system)
	NMNAT2 affects MAPT phosphorylation by regulating PPP2CA activity
	novel function for PSEN1 in modulating NUP62 expression to control the proteostasis of MAPT
	YWHAZ has a role in the fibrillization of MAPT in Alzheimer brain, and MAPT phosphorylation does not affect YWHAZ-induced MAPT aggregation
	EFHD2 co-aggregates and interacts with known neuropathological proteins, such as MAPT, C9orf72, and LRRK2
	regulatory role of DYRK1A in controlling MAPT and SNCA
	CX3CR1 is a novel target for the clearance of extracellular MAPT
	CX3CR1/CX3CL1 axis plays a key role in the phagocytosis of MAPT by microglia and that it is affected as Alzheimer disease progresses
	DNAJA2 levels were correlated with MAPT pathology in human brains, supporting the idea that it is an important regulator of MAPT homeostasis
	DNAJA2 is an unexpected, but potent, inhibitor of MAPT aggregation

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
	increase in MAPT phosphorylation at Ser262 through MARK2 contributes to MAPT-mediated neurodegeneration under a pathological condition in which axonal mitochondria is depleted

ASSOCIATED DISORDERS

corresponding disease(s)

FTDP17 , PSRP , DEL17Q21 , DUP17Q21

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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 constitutional     --over   increased levels of neuronal MAPT are an important factor in the progression of tauopathy, and ER stress-induced increase in total MAPT protein is due to a delay in its degradation

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