MAPT

Summary

MAPT (microtubule associated protein tau, HGNC:6893) is a protein-coding gene on chromosome 17q21.31, encoding Microtubule-associated protein tau (P10636). Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity.

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.

Source: NCBI Gene 4137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): late-onset Parkinson disease (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 124
• Clinical variants (ClinVar): 602 total — 27 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 160
• Druggable target: yes — 449 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001377265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6893
Approved symbol	MAPT
Name	microtubule associated protein tau
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Aliases	MTBT1, tau, PPND, FTDP-17, TAU, MSTD, MTBT2, FLJ31424, MGC138549, PPP1R103, tau-40, Tau-PHF6
Ensembl gene	ENSG00000186868
Ensembl biotype	protein_coding
OMIM	157140
Entrez	4137

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 34 protein_coding, 6 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay, 6 retained_intron

ENST00000262410, ENST00000334239, ENST00000344290, ENST00000351559, ENST00000415613, ENST00000420682, ENST00000431008, ENST00000446361, ENST00000535772, ENST00000570299, ENST00000571311, ENST00000571987, ENST00000572440, ENST00000574436, ENST00000576518, ENST00000577017, ENST00000680542, ENST00000680674, ENST00000703922, ENST00000703923, ENST00000703924, ENST00000703974, ENST00000703975, ENST00000703976, ENST00000703977, ENST00000703978, ENST00000703979, ENST00000703980, ENST00000703981, ENST00000703982, ENST00000884777, ENST00000884778, ENST00000884779, ENST00000884780, ENST00000884781, ENST00000884782, ENST00000884783, ENST00000884784, ENST00000884785, ENST00000884786, ENST00000884787, ENST00000884788, ENST00000972111, ENST00000972112, ENST00000972113, ENST00000972114, ENST00000972115, ENST00000972116, ENST00000972117, ENST00000972118, ENST00000972119, ENST00000972120

RefSeq mRNA: 12 — MANE Select: NM_001377265 NM_001123066, NM_001123067, NM_001203251, NM_001203252, NM_001377265, NM_001377266, NM_001377267, NM_001377268, NM_005910, NM_016834, NM_016835, NM_016841

CCDS: CCDS11499, CCDS11500, CCDS11501, CCDS11502, CCDS45715, CCDS45716, CCDS56033, CCDS92345, CCDS92346, CCDS92347

Canonical transcript exons

ENST00000262410 — 13 exons

Exon	Start	End
ENSE00001291240	46023956	46028334
ENSE00002405491	46014243	46014324
ENSE00002409189	46010310	46010402
ENSE00002410720	45989878	45990075
ENSE00002672395	45982866	45983930
ENSE00003549966	45962321	45962470
ENSE00003570976	46018618	46018730
ENSE00003598892	45971859	45971945
ENSE00003611335	45987040	45987095
ENSE00003634058	45996399	45996664
ENSE00003658894	45978375	45978440
ENSE00003682122	45991460	45991586
ENSE00003900976	45894554	45894686

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 99.52.

FANTOM5 (CAGE): breadth broad, TPM avg 34.2068 / max 1482.6267, expressed in 870 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161306	23.3378	717
161305	5.1808	597
161307	3.0812	334
161309	1.6276	147
161308	0.3571	101
161304	0.2721	77
161311	0.2095	90
161317	0.0638	31
161320	0.0449	21
161310	0.0321	11

Top tissues by expression

143 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.52	gold quality
superior frontal gyrus	UBERON:0002661	98.76	gold quality
prefrontal cortex	UBERON:0000451	98.51	gold quality
frontal cortex	UBERON:0001870	98.45	gold quality
frontal lobe	UBERON:0016525	98.45	gold quality
right frontal lobe	UBERON:0002810	98.32	gold quality
cerebellum	UBERON:0002037	98.29	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.29	gold quality
cerebellar cortex	UBERON:0002129	98.28	gold quality
cerebellar hemisphere	UBERON:0002245	98.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	98.08	gold quality
primary visual cortex	UBERON:0002436	98.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.88	gold quality
cerebral cortex	UBERON:0000956	97.87	gold quality
anterior cingulate cortex	UBERON:0009835	97.39	gold quality
hypothalamus	UBERON:0001898	97.34	gold quality
Ammon’s horn	UBERON:0001954	97.33	gold quality
temporal lobe	UBERON:0001871	97.32	gold quality
amygdala	UBERON:0001876	97.29	gold quality
brain	UBERON:0000955	96.91	gold quality
putamen	UBERON:0001874	96.68	gold quality
corpus callosum	UBERON:0002336	96.61	gold quality
caudate nucleus	UBERON:0001873	96.58	gold quality
substantia nigra	UBERON:0002038	96.45	gold quality
nucleus accumbens	UBERON:0001882	96.36	gold quality
embryo	UBERON:0000922	95.99	gold quality
ganglionic eminence	UBERON:0004023	95.99	gold quality
gastrocnemius	UBERON:0001388	95.59	gold quality
skeletal muscle tissue	UBERON:0001134	95.52	gold quality
skeletal muscle organ	UBERON:0014892	94.64	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	63.25
E-GEOD-93593	yes	18.41
E-ANND-3	no	1.59

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOS	Repression

Upstream regulators (CollecTRI, top): AR, DLX3, TFAP2A

miRNA regulators (miRDB)

133 targeting MAPT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-4420	99.82	70.08	1624

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Associated with etilogical mechanism of Alzheimer’s disease. (PMID:11831025)
• a biomarker for Alzheimer disease (PMID:11831556)
• Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. (PMID:11837744)
• The glycosylation of tau is an early abnormality that can facilitate the subsequent abnormal hyperphosphorylation of tau in Alzheimer’s disease brain. (PMID:11852060)
• This suggests that usually FTDP-17 and PSP, including the rare familial form of PSP, are likely to be separate conditions and that usually PSP and typical PSP-like syndromes are not due to mutations in tau. (PMID:11861703)
• The tau H1 haplotype is associated with increased risk of Parkinson disease in a Norwegian population. (PMID:11958849)
• Modelling Alzheimer-specific abnormal Tau phosphorylation independently of GSK3beta and PKA kinase activities. (PMID:11959122)
• Tau is essential to beta -amyloid-induced neurotoxicity (PMID:11959919)
• additional regulatory sequences rugulating tau exon 10 splicing (PMID:12000767)
• Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. (PMID:12070658)
• These results provide strong evidence suggesting that MAP2c and tau stabilize microtubules by binding along individual protofilaments, possibly by bridging the tubulin interfaces. (PMID:12082079)
• Pick’s disease is characterized by accumulation of Pick bodies in the hippocampus and cortex, and by the presence of microtubule-binding repeat tau pathology in gray and white matter, distinguishing this tauopathy from other neurodegenerative disorders. (PMID:12112079)
• Results suggest that binding of tau to DNA occurs in an aggregation-dependent, and a phosphorylation-independent, manner. (PMID:12144513)
• In aging and sporadic Alzheimer’s disease, severe tau pathology (stage 7 to stage 10) correlates well with a huge and widespread Abeta burden. (PMID:12177374)
• new insights into the conformation of tau in the soluble state and after incorporation into paired helical filaments (PMID:12198126)
• no evidence seen for association of tau gene polymorphism with transmissible spongiform encephalopathies (PMID:12212558)
• biochemical analysis in argyrophilic grain disease, Alzheimer’s disease, and Pick’s disease (PMID:12368187)
• Expression of mutant human tau isoform in transgenic mice resulted in the development of congophilic hyperphosphorylated tau inclusions in forebrain neurons. (PMID:12368474)
• phosphorylation by cdk5 and GSK-3beta (PMID:12387894)
• two phosphorylation sites (serines 262 and 356) were identified in the tubulin binding sites. When tau was phosphorylated by CaM kinase II, the binding of tau to taxol-stabilized microtubules was remarkably impaired. (PMID:12464279)
• REVIEW: tau dysfunction can lead to neurodegeneration and the development of clinical symptoms (PMID:12470988)
• This is a possible candidate gene in frontal lobe dementia. (PMID:12476321)
• The phenotype of pallidopontonigral degeneration (PPND) resulting from N279K mutation of tau includes dysfunction of the autonomic nervous system, correlating with the duration of illness and clinical and functional severity of parkinsonism. (PMID:12492138)
• Repeat motifs of this protein bind to the insides of microtubules in the absence of taxol (PMID:12505985)
• Tau isoforms are O-GlcNAc modified (a marker of healthy brain Tau) and a balance occurs between phosphorylation, glycosylation and nuclear localization (PMID:12527113)
• can prevent DNA from thermal denaturation, improve renaturation and protect DNA from damage induced by free radicals (PMID:12573250)
• The interaction of the amino terminus of tau with its microtubule-binding repeat regions, creating a conformation similar to that recognized by the monoclonal antibody Alz50, is very likely a propolymerization state of the tau molecule. (PMID:12590615)
• Significant overrepresentation of the tau H1/H1 genotype, also found in progressive supranuclear palsy and corticobasal degeneration, was found in the primary progresssive aphasia group. (PMID:12629248)
• Paired helical filament-tau inhibits proteasome activity in Alzheimer disease brain (PMID:12641733)
• results implicate the human tau gene as a target gene for the alternative splicing regulator Tra2 beta protein, suggesting that Tra2 beta may play a role in aberrant tau exon 10 alternative splicing (PMID:12649279)
• This protein binds to DNA but not single-stranded DNA. (PMID:12678504)
• A positive association between the H1 haplotype and frontotemporal dementia was found, consistent with the hypothesis that the tau gene, or nearby gene on the H1 haplotype, is a risk factor for frontotemporal dementia (PMID:12710929)
• results suggest that interactions between alpha-synuclein and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases (PMID:12714745)
• Sequence variations in intronic or regulatory regions of tau may have previously unrecognized consequences leading to tau dysfunction and neurodegeneration. (PMID:12756133)
• cdk5 can initiate a major impact on tau pathology progression that probably involves several kinases. (PMID:12765608)
• Frontotemporal dementia and parkinsonism with the P301S tau gene mutation in a Jewish family. (PMID:12796837)
• In this study the presence of tau and 14-3-3 proteins in GCIs of 21 patients with MSA was investigated. (PMID:12811584)
• MAPT mutations are not connected with most of the frontotemporal dementia cases in the Polish population. (PMID:12826737)
• The authors describe a case of clinically diagnosed young onset progressive supranuclear palsy (PSP) with symptom onset at 40 years of age, no family history and tau exon 10 +16 mutation (MAPT, IVS10, C-U, +16) (PMID:12847166)
• native filaments from brain and filaments assembled in vitro from expressed tau protein have a clear cross-beta structure (PMID:12853572)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	maptb	ENSDARG00000087616
danio_rerio	mapta	ENSDARG00000089314
mus_musculus	Mapt	ENSMUSG00000018411
rattus_norvegicus	Mapt	ENSRNOG00000005133

Paralogs (1): MAP2 (ENSG00000078018)

Protein

Protein identifiers

Microtubule-associated protein tau — P10636 (reviewed: P10636)

Alternative names: Neurofibrillary tangle protein, Paired helical filament-tau

All UniProt accessions (5): A0A7I2PJZ2, A0A7I2PLE3, A0A7P0T936, P10636, I3L2Z2

UniProt curated annotations — full annotation on UniProt →

Function. Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. 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. 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.

Subunit / interactions. Interacts with MARK1, MARK2, MARK3 and MARK4. Interacts with PSMC2 through SQSTM1. Interacts with SQSTM1 when polyubiquitinated. Interacts with FKBP4. Binds to CSNK1D. Interacts with SGK1. Interacts with EPM2A; the interaction dephosphorylates MAPT at Ser-396. Interacts with PIN1. Interacts with LRRK2. Interacts with LRP1, leading to endocytosis; this interaction is reduced in the presence of LRPAP1/RAP.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Cytoskeleton. Cell projection. Axon. Dendrite. Secreted.

Tissue specificity. Expressed in neurons. Isoform PNS-tau is expressed in the peripheral nervous system while the others are expressed in the central nervous system.

Post-translational modifications. 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. 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. 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. 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.

Disease relevance. 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 1 (FTD1) [MIM:600274] 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. The disease is caused by variants affecting the gene represented in this entry. Pick disease of the brain (PIDB) [MIM:172700] 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. The disease is caused by variants affecting the gene represented in this entry. 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) [MIM:601104] 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. The disease is caused by variants affecting the gene represented in this entry. Parkinson-dementia syndrome (PARDE) [MIM:260540] A syndrome characterized by parkinsonism, tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The tau/MAP repeat binds to tubulin. Type I isoforms contain 3 repeats while type II isoforms contain 4 repeats.

Isoforms (9)

UniProt ID	Names	Canonical?
P10636-1	PNS-tau	yes
P10636-2	Fetal-tau, 0N3R
P10636-3	Tau-A
P10636-4	Tau-B, 1N3R
P10636-5	Tau-C, Tau-3, 2N3R
P10636-6	Tau-D, 0N4R
P10636-7	Tau-E, 1N4R
P10636-8	Tau-F, Tau-4, 2N4R
P10636-9	Tau-G

RefSeq proteins (12): NP_001116538, NP_001116539, NP_001190180, NP_001190181, NP_001364194, NP_001364195, NP_001364196, NP_001364197, NP_005901, NP_058518, NP_058519, NP_058525 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001084	MAP_tubulin-bd_rpt	Repeat
IPR002955	Tau	Family
IPR027324	MAP2/MAP4/Tau	Family

Pfam: PF00418

UniProt features (234 total): modified residue 64, site 31, sequence variant 30, strand 22, glycosylation site 16, cross-link 16, compositionally biased region 14, mutagenesis site 14, splice variant 8, sequence conflict 6, repeat 4, region of interest 3, turn 2, initiator methionine 1, chain 1, disulfide bond 1, helix 1

Structure

Experimental structures (PDB)

293 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6ODG	X-RAY DIFFRACTION	1
8KDX	X-RAY DIFFRACTION	1.01
5K7N	ELECTRON CRYSTALLOGRAPHY	1.1
9GG8	X-RAY DIFFRACTION	1.1
9GG7	X-RAY DIFFRACTION	1.24
5V5C	ELECTRON CRYSTALLOGRAPHY	1.25
6FAU	X-RAY DIFFRACTION	1.25
8GCK	X-RAY DIFFRACTION	1.37
4Y5I	X-RAY DIFFRACTION	1.4
6FAV	X-RAY DIFFRACTION	1.4
6FAW	X-RAY DIFFRACTION	1.4
9GHK	X-RAY DIFFRACTION	1.42
6FBW	X-RAY DIFFRACTION	1.45
9FVG	X-RAY DIFFRACTION	1.45
9FVH	X-RAY DIFFRACTION	1.45
5E2W	X-RAY DIFFRACTION	1.5
5V5B	ELECTRON CRYSTALLOGRAPHY	1.5
6FBY	X-RAY DIFFRACTION	1.5
9FVN	X-RAY DIFFRACTION	1.5
2ON9	X-RAY DIFFRACTION	1.51
4NP8	X-RAY DIFFRACTION	1.51
8OP0	X-RAY DIFFRACTION	1.54
9FVI	X-RAY DIFFRACTION	1.55
6PXR	X-RAY DIFFRACTION	1.56
9FVP	X-RAY DIFFRACTION	1.58
4TQE	X-RAY DIFFRACTION	1.6
9FS4	X-RAY DIFFRACTION	1.6
9GFA	X-RAY DIFFRACTION	1.6
9QNK	X-RAY DIFFRACTION	1.6
5E2V	X-RAY DIFFRACTION	1.64

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10636-F1	49.56	0.00

Antibody-complex structures (SAbDab): 27 — 4GLR, 4TQE, 5DMG, 5E2V, 5E2W, 5MO3, 5MP1, 5MP3, 5MP5, 5ZIA, 5ZV3, 6BB4, 6DC8, 6DC9, 6DCA, 6GK7, 6GK8, 6H06, 6LRA, 6PXR, 6XLI, 7EYC, 7KQK, 8OP0, 8OPI (+2 more)

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (31): 24 (not glycated); 44 (not glycated); 67 (not glycated); 381 (not glycated); 391 (not glycated); 392 (not glycated); 394 (not glycated); 465 (not glycated); 497 (not glycated); 507 (not glycated); 541 (not glycated); 557 (not glycated) …

Post-translational modifications (80): 641, 648, 660, 664, 666, 669, 673, 686, 702, 711, 713, 717, 720, 721, 726, 733, 739, 744, 44, 571 …

Disulfide bonds (1): 608–639

Glycosylation sites (16): 87, 383, 467, 480, 491, 525, 542, 551, 555, 576, 597, 598, 664, 670, 686, 717

Mutagenesis-validated functional residues (14):

Position	Phenotype
515	no association with plasma membrane.
516	no association with plasma membrane.
519	no association with plasma membrane.
531	no decrease in microtubule-binding and nucleation activity after in vitro phosphorylation of mutant protein.
548	50% decrease in microtubule-binding after in vitro phosphorylation of mutant protein.
548	no association with plasma membrane.
552	70% decrease in microtubule-binding after in vitro phosphorylation of mutant protein.
552	no association with plasma membrane.
579	8% decrease in microtubule-binding after in vitro phosphorylation of mutant protein.
713	no association with plasma membrane.
721	no association with plasma membrane.
726	no association with plasma membrane.
730	no association with plasma membrane.
739	no association with plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-9619483	Activation of AMPK downstream of NMDARs
R-HSA-9833482	PKR-mediated signaling
R-HSA-109581	Apoptosis
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-5357801	Programmed Cell Death
R-HSA-75153	Apoptotic execution phase

MSigDB gene sets: 699 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MEMORY, GOBP_CHROMOSOME_ORGANIZATION, GNF2_RTN1, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, PAX4_01, GOBP_NEURON_PROJECTION_EXTENSION

GO Biological Process (52): microtubule cytoskeleton organization (GO:0000226), microglial cell activation (GO:0001774), DNA damage response (GO:0006974), cell-cell signaling (GO:0007267), synapse assembly (GO:0007416), learning or memory (GO:0007611), memory (GO:0007613), response to lead ion (GO:0010288), regulation of autophagy (GO:0010506), negative regulation of gene expression (GO:0010629), negative regulation of mitochondrial membrane potential (GO:0010917), rRNA metabolic process (GO:0016072), axonal transport of mitochondrion (GO:0019896), central nervous system neuron development (GO:0021954), regulation of microtubule polymerization or depolymerization (GO:0031110), regulation of microtubule polymerization (GO:0031113), positive regulation of microtubule polymerization (GO:0031116), cytoplasmic microtubule organization (GO:0031122), neuron projection development (GO:0031175), positive regulation of superoxide anion generation (GO:0032930), regulation of chromosome organization (GO:0033044), stress granule assembly (GO:0034063), cellular response to heat (GO:0034605), cellular response to reactive oxygen species (GO:0034614), positive regulation of axon extension (GO:0045773), microtubule polymerization (GO:0046785), astrocyte activation (GO:0048143), regulation of synaptic plasticity (GO:0048167), intracellular distribution of mitochondria (GO:0048312), generation of neurons (GO:0048699), synapse organization (GO:0050808), regulation of calcium-mediated signaling (GO:0050848), protein polymerization (GO:0051258), protein homooligomerization (GO:0051260), regulation of microtubule-based movement (GO:0060632), axon development (GO:0061564), regulation of microtubule cytoskeleton organization (GO:0070507), plus-end-directed organelle transport along microtubule (GO:0072386), regulation of mitochondrial fission (GO:0090140), negative regulation of mitochondrial fission (GO:0090258)

GO Molecular Function (26): DNA binding (GO:0003677), minor groove of adenine-thymine-rich DNA binding (GO:0003680), double-stranded DNA binding (GO:0003690), single-stranded DNA binding (GO:0003697), RNA binding (GO:0003723), actin binding (GO:0003779), enzyme inhibitor activity (GO:0004857), microtubule binding (GO:0008017), SH3 domain binding (GO:0017124), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), apolipoprotein binding (GO:0034185), dynactin binding (GO:0034452), phosphatidylinositol binding (GO:0035091), identical protein binding (GO:0042802), sequence-specific DNA binding (GO:0043565), protein-folding chaperone binding (GO:0051087), protein phosphatase 2A binding (GO:0051721), Hsp90 protein binding (GO:0051879), lipoprotein particle binding (GO:0071813), histone-dependent DNA binding (GO:0099077), microtubule lateral binding (GO:0099609), phosphatidylinositol bisphosphate binding (GO:1902936), protein binding (GO:0005515), tubulin binding (GO:0015631)

GO Cellular Component (28): extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), microtubule (GO:0005874), plasma membrane (GO:0005886), microtubule cytoskeleton (GO:0015630), axon (GO:0030424), dendrite (GO:0030425), growth cone (GO:0030426), axolemma (GO:0030673), nuclear periphery (GO:0034399), cytoplasmic ribonucleoprotein granule (GO:0036464), somatodendritic compartment (GO:0036477), neuron projection (GO:0043005), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), cell body (GO:0044297), main axon (GO:0044304), membrane raft (GO:0045121), tubulin complex (GO:0045298), glial cell projection (GO:0097386), neurofibrillary tangle (GO:0097418), axon cytoplasm (GO:1904115), cytoskeleton (GO:0005856), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Apoptotic cleavage of cellular proteins	1
Post NMDA receptor activation events	1
Antimicrobial mechanism of IFN-stimulated genes	1
Programmed Cell Death	1
Apoptotic execution phase	1
Apoptosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein binding	5
DNA binding	3
cytoplasm	3
neuron development	2
microtubule polymerization	2
nucleic acid binding	2
cytoskeletal protein binding	2
intracellular membrane-bounded organelle	2
neuron projection	2
cytoskeleton organization	1
microtubule-based process	1
leukocyte activation involved in inflammatory response	1
macrophage activation	1
glial cell activation	1
cellular response to stress	1
cell communication	1
signaling	1
nervous system development	1
cell junction assembly	1
synapse organization	1
behavior	1
cognition	1
learning or memory	1
response to metal ion	1
autophagy	1
regulation of catabolic process	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
negative regulation of membrane potential	1
regulation of mitochondrial membrane potential	1
RNA metabolic process	1
mitochondrion transport along microtubule	1
axonal transport	1
axon cytoplasm	1
central nervous system neuron differentiation	1
microtubule polymerization or depolymerization	1
regulation of microtubule cytoskeleton organization	1
regulation of microtubule polymerization or depolymerization	1

Protein interactions and networks

STRING

5558 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPT	APP	P05067	986
MAPT	VDAC1	P21796	974
MAPT	APOE	P02649	973
MAPT	SNCA	P37840	971
MAPT	TARDBP	Q13148	970
MAPT	FYN	P06241	958
MAPT	CDK5	Q00535	948
MAPT	GSK3B	P49841	943
MAPT	PSEN1	P49768	933
MAPT	YWHAQ	P27348	903
MAPT	FUS	P35637	889
MAPT	GRN	P23781	886
MAPT	PSEN2	P49810	883
MAPT	C9orf72	Q96LT7	852
MAPT	PRNP	P04156	834

IntAct

160 interactions, top by confidence:

A	B	Type	Score
PRNP	APP	psi-mi:“MI:0914”(association)	0.770
APP	MAPT	psi-mi:“MI:0217”(phosphorylation reaction)	0.750
APP	MAPT	psi-mi:“MI:0407”(direct interaction)	0.750
MAPT	APP	psi-mi:“MI:0407”(direct interaction)	0.750
MAPT	APP	psi-mi:“MI:0403”(colocalization)	0.750
APP	MAPT	psi-mi:“MI:0915”(physical association)	0.750
MAPT	YWHAZ	psi-mi:“MI:0915”(physical association)	0.720
YWHAZ	MAPT	psi-mi:“MI:0915”(physical association)	0.720
MAPT	YWHAZ	psi-mi:“MI:0914”(association)	0.720
YWHAZ	MAPT	psi-mi:“MI:0914”(association)	0.720
MAPT	APP	psi-mi:“MI:0407”(direct interaction)	0.710
APP	MAPT	psi-mi:“MI:0407”(direct interaction)	0.710
MAPT	MAPT	psi-mi:“MI:0407”(direct interaction)	0.670
HSPA8	MAPT	psi-mi:“MI:0407”(direct interaction)	0.670
MAPT	MAPT	psi-mi:“MI:0915”(physical association)	0.670
MAPT		psi-mi:“MI:0914”(association)	0.640

BioGRID (1571): MAPT (Biochemical Activity), YWHAZ (Affinity Capture-Western), YWHAQ (Affinity Capture-Western), MAPT (Affinity Capture-Western), Ywhaz (Reconstituted Complex), MAPT (Biochemical Activity), ABL1 (Affinity Capture-Western), MAPT (Biochemical Activity), MAPT (Biochemical Activity), MAPT (Biochemical Activity), MAPT (Biochemical Activity), MAPT (Biochemical Activity), MAPT (Reconstituted Complex), MAPT (Biochemical Activity), DCTN1 (Two-hybrid)

ESM2 similar proteins: A0A1B0GUA9, A2TJV2, A4FU49, A6NDB9, A6X8Z5, D3ZAQ5, P0C671, P10636, P10637, P48681, P58871, Q14676, Q2YDF7, Q3MI48, Q4R729, Q5EBJ4, Q5PSV9, Q5S6V2, Q5SWP3, Q5TM66, Q5TM68, Q5U2M8, Q5YCV9, Q5YCW0, Q5YCW1, Q640N3, Q68A65, Q68DA7, Q6NYC8, Q6ZW13, Q767L8, Q7YR40, Q7Z6I6, Q811Q2, Q8BHB9, Q8BHW6, Q8BQ30, Q8CB87, Q8CC96, Q8IXJ9

Diamond homologs: O02828, P10636, P10637, P11137, P15146, P19332, P20357, P27546, P27816, P29172, P36225, P57786, Q5M7W5, Q5S6V2, Q5YCV9, Q5YCW0, Q5YCW1, Q6TS35, Q9MYX8

SIGNOR signaling

138 interactions.

A	Effect	B	Mechanism
CSNK1D	down-regulates	MAPT	phosphorylation
FYN	down-regulates	MAPT	phosphorylation
PPP2R1A	down-regulates	MAPT	dephosphorylation
TTBK1	down-regulates	MAPT	phosphorylation
GSK3B	down-regulates	MAPT	phosphorylation
SYK	down-regulates	MAPT	phosphorylation
SGK1	down-regulates	MAPT	phosphorylation
PP2B	up-regulates	MAPT	dephosphorylation
MAPK14	up-regulates	MAPT	phosphorylation
CDK5	down-regulates	MAPT	phosphorylation
CHEK2	down-regulates	MAPT	phosphorylation
DYRK1A	down-regulates	MAPT	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 108 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	59.3×	1e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	43.6×	8e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	43.6×	8e-06
Activation of BH3-only proteins	6	38.7×	2e-06
Dengue Virus Genome Translation and Replication	6	24.7×	1e-05
Intrinsic Pathway for Apoptosis	6	22.8×	2e-05
FOXO-mediated transcription	5	21.8×	2e-04
RHO GTPases activate PKNs	5	20.6×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of protein ubiquitination	6	17.3×	4e-04
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	7	14.9×	2e-04
positive regulation of protein localization to plasma membrane	5	13.7×	3e-03
intracellular protein localization	10	10.6×	4e-05
protein autophosphorylation	6	8.8×	4e-03
central nervous system development	7	8.2×	2e-03
neuron migration	6	8.1×	5e-03
protein phosphorylation	10	6.9×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

602 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	8
Uncertain significance	250
Likely benign	152
Benign	94

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
14245	NM_001377265.1(MAPT):c.2078C>T (p.Pro693Leu)	Pathogenic
14246	NM_001377265.1(MAPT):c.1991G>T (p.Gly664Val)	Pathogenic
14247	NM_001377265.1(MAPT):c.2392C>T (p.Arg798Trp)	Pathogenic
14248	NM_001377265.1(MAPT):c.2091+14C>T	Pathogenic
14251	NM_001377265.1(MAPT):c.2091+1G>A	Pathogenic
14252	NM_001377265.1(MAPT):c.2185G>A (p.Val729Met)	Pathogenic
14253	NM_001377265.1(MAPT):c.2013T>G (p.Asn671Lys)	Pathogenic
14254	NM_001377265.1(MAPT):c.2090G>A (p.Ser697Asn)	Pathogenic
14257	NM_001377265.1(MAPT):c.2064T>C (p.Asn688=)	Pathogenic
14258	NM_001377265.1(MAPT):c.2201A>T (p.Glu734Val)	Pathogenic
14259	NM_001377265.1(MAPT):c.1946A>C (p.Lys649Thr)	Pathogenic
14260	NM_001377265.1(MAPT):c.2282A>T (p.Lys761Ile)	Pathogenic
14262	NM_001377265.1(MAPT):c.2135C>T (p.Ser712Phe)	Pathogenic
14263	NM_001377265.1(MAPT):c.14G>T (p.Arg5Leu)	Pathogenic
14266	NM_001377265.1(MAPT):c.1972C>G (p.Leu658Val)	Pathogenic
14267	NM_001377265.1(MAPT):c.2231C>T (p.Ser744Leu)	Pathogenic
14268	NM_001377265.1(MAPT):c.2126A>T (p.Lys709Met)	Pathogenic
14269	NM_001377265.1(MAPT):c.2084G>T (p.Gly695Val)	Pathogenic
2573094	NM_001377265.1(MAPT):c.2266C>T (p.Pro756Ser)	Pathogenic
564448	GRCh37/hg19 17q21.31(chr17:43688308-44163085)x1	Pathogenic
98212	NM_001377265.1(MAPT):c.1999-10G>T	Pathogenic
98218	NM_001377265.1(MAPT):c.2091+3G>A	Pathogenic
98219	NM_001377265.1(MAPT):c.2091+11T>C	Pathogenic
98221	NM_001377265.1(MAPT):c.2091+13A>G	Pathogenic
98222	NM_001377265.1(MAPT):c.2091+16C>T	Pathogenic
98226	NM_001377265.1(MAPT):c.2120T>G (p.Leu707Arg)	Pathogenic
98243	NM_001377265.1(MAPT):c.2060ATA[1] (p.Asn688del)	Pathogenic
14256	NM_001377265.1(MAPT):c.2077C>T (p.Pro693Ser)	Likely pathogenic
2049744	NM_001377265.1(MAPT):c.2091+16C>G	Likely pathogenic
3075676	NM_001377265.1(MAPT):c.2077C>G (p.Pro693Ala)	Likely pathogenic

SpliceAI

3502 predictions. Top by Δscore:

Variant	Effect	Δscore
17:45894684:CAGGT:C	donor_loss	1.0000
17:45894685:AGGTA:A	donor_loss	1.0000
17:45894686:GGTA:G	donor_loss	1.0000
17:45894687:G:GA	donor_loss	1.0000
17:45962316:CCCA:C	acceptor_loss	1.0000
17:45962317:CCA:C	acceptor_loss	1.0000
17:45962318:CA:C	acceptor_loss	1.0000
17:45962319:A:AC	acceptor_loss	1.0000
17:45962319:A:AG	acceptor_gain	1.0000
17:45962319:AGGT:A	acceptor_gain	1.0000
17:45962320:G:GA	acceptor_gain	1.0000
17:45962320:GGT:G	acceptor_gain	1.0000
17:45962320:GGTG:G	acceptor_gain	1.0000
17:45962467:AAAG:A	donor_loss	1.0000
17:45962468:AAGGT:A	donor_loss	1.0000
17:45962471:GTT:G	donor_loss	1.0000
17:45978354:A:AG	acceptor_gain	1.0000
17:45978354:ATTT:A	acceptor_gain	1.0000
17:45978355:T:G	acceptor_gain	1.0000
17:45978357:T:A	acceptor_gain	1.0000
17:45978360:T:A	acceptor_gain	1.0000
17:45978365:C:G	acceptor_gain	1.0000
17:45978436:CCAAG:C	donor_loss	1.0000
17:45978437:CAAGG:C	donor_loss	1.0000
17:45978438:AAGG:A	donor_loss	1.0000
17:45978439:AGGT:A	donor_loss	1.0000
17:45978440:GGTC:G	donor_loss	1.0000
17:45978441:GTCA:G	donor_loss	1.0000
17:45978442:T:G	donor_loss	1.0000
17:45991452:A:AG	acceptor_gain	1.0000

AlphaMissense

5567 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:46014315:C:G	H647D	1.000
17:46023977:T:C	F695L	1.000
17:46023979:C:A	F695L	1.000
17:46023979:C:G	F695L	1.000
17:45996528:T:A	V546D	0.999
17:45996609:T:A	V573D	0.999
17:45996637:C:A	N582K	0.999
17:45996637:C:G	N582K	0.999
17:45996644:C:G	H585D	0.999
17:46010317:T:A	I594K	0.999
17:46010347:T:A	V604D	0.999
17:46014250:T:A	I625K	0.999
17:46014250:T:G	I625R	0.999
17:46014291:T:C	C639R	0.999
17:46014308:C:A	N644K	0.999
17:46014308:C:G	N644K	0.999
17:46014310:T:A	I645N	0.999
17:46018657:T:C	F663S	0.999
17:46018704:C:G	H679D	0.999
17:46023972:T:C	L693P	0.999
17:46023990:C:A	A699D	0.999
17:46024152:T:C	L753P	0.999
17:45996522:C:A	A544E	0.998
17:45996530:C:A	R547S	0.998
17:45996617:A:G	K576E	0.998
17:45996619:G:C	K576N	0.998
17:45996619:G:T	K576N	0.998
17:45996624:G:A	G578D	0.998
17:45996626:T:C	S579P	0.998
17:45996635:A:G	N582D	0.998

dbSNP variants (sampled 300 via entrez): RS1000018617 (17:45937693 C>T), RS1000023912 (17:45897484 T>C), RS1000032592 (17:45919337 C>A,T), RS1000049290 (17:45897720 ACCT>A), RS1000056502 (17:46019665 G>A,C), RS1000059184 (17:45896056 C>A,G,T), RS1000108399 (17:46019953 A>C), RS1000128120 (17:45938646 T>A), RS1000138350 (17:45980501 C>G), RS1000164595 (17:45992005 C>T), RS1000165676 (17:45950246 C>T), RS1000166162 (17:46003085 T>C), RS1000199533 (17:45963325 A>T), RS1000224021 (17:45953345 A>G), RS1000235737 (17:45902204 C>G,T)

Disease associations

OMIM: gene MIM:157140 | disease phenotypes: MIM:168600, MIM:172700, MIM:260540, MIM:601104, MIM:600274

GenCC curated gene-disease

Disease	Classification	Inheritance
late-onset Parkinson disease	Strong	Autosomal dominant
Pick disease	Strong	Autosomal dominant
semantic dementia	Strong	Autosomal dominant
supranuclear palsy, progressive, 1	Strong	Autosomal dominant
progressive supranuclear palsy-parkinsonism syndrome	Moderate	Autosomal recessive

Mondo (11): frontotemporal dementia (MONDO:0017276), late-onset Parkinson disease (MONDO:0008199), Pick disease (MONDO:0008243), progressive supranuclear palsy-parkinsonism syndrome (MONDO:0009839), supranuclear palsy, progressive, 1 (MONDO:0010997), prostate cancer (MONDO:0008315), parkinsonian disorder (MONDO:0021095), semantic dementia (MONDO:0010857), Alzheimer disease (MONDO:0004975), multiple system atrophy (MONDO:0007803), dementia (MONDO:0001627)

Orphanet (11): Frontotemporal dementia (Orphanet:282), Classic progressive supranuclear palsy syndrome (Orphanet:240071), Progressive supranuclear palsy-predominant parkinsonism syndrome (Orphanet:240085), Hereditary late-onset Parkinson disease (Orphanet:411602), Progressive supranuclear palsy (Orphanet:683), Atypical progressive supranuclear palsy syndrome (Orphanet:99750), Familial prostate cancer (Orphanet:1331), Semantic dementia (Orphanet:100069), Early-onset autosomal dominant Alzheimer disease (Orphanet:1020), Multiple system atrophy (Orphanet:102), NON RARE IN EUROPE: Alzheimer disease (Orphanet:238616)

HPO phenotypes

160 total (30 of 160 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000012	Urinary urgency
HP:0000298	Mask-like facies
HP:0000474	Thickened nuchal skin fold
HP:0000496	Abnormality of eye movement
HP:0000511	Vertical supranuclear gaze palsy
HP:0000514	Slow saccadic eye movements
HP:0000570	Abnormal saccadic eye movements
HP:0000571	Hypometric saccades
HP:0000597	Ophthalmoparesis
HP:0000605	Supranuclear gaze palsy
HP:0000613	Photophobia
HP:0000622	Blurred vision
HP:0000633	Decreased lacrimation
HP:0000643	Blepharospasm
HP:0000651	Diplopia
HP:0000657	Oculomotor apraxia
HP:0000658	Eyelid apraxia
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000726	Dementia
HP:0000727	Frontal lobe dementia
HP:0000733	Motor stereotypy

GWAS associations

124 associations (top):

Study	Trait	p-value
GCST000528_6	Parkinson’s disease	2.000000e-16
GCST000567_1	Parkinson’s disease	6.000000e-08
GCST000772_3	Parkinson’s disease	1.000000e-06
GCST000855_1	Parkinson’s disease	7.000000e-12
GCST000959_11	Parkinson’s disease	1.000000e-28
GCST001116_6	Progressive supranuclear palsy	9.000000e-18
GCST001116_8	Progressive supranuclear palsy	2.000000e-118
GCST001126_3	Parkinson’s disease	3.000000e-14
GCST001445_4	Parkinson’s disease	8.000000e-52
GCST001482_23	Lumbar spine bone mineral density	5.000000e-11
GCST001483_2	Intracranial volume	8.000000e-15
GCST001484_2	Head circumference (infant)	4.000000e-06
GCST001968_12	Interstitial lung disease	9.000000e-14
GCST001974_3	Idiopathic pulmonary fibrosis	6.000000e-09
GCST002353_6	Parkinson’s disease	2.000000e-06
GCST002353_7	Parkinson’s disease	8.000000e-07
GCST002455_2	Parkinson’s disease	8.000000e-09
GCST002544_5	Parkinson’s disease	2.000000e-48
GCST002756_10	Subcortical brain region volumes	1.000000e-08
GCST002817_27	Alzheimer’s disease in APOE e4- carriers	6.000000e-09
GCST002970_1	Corticobasal degeneration	1.000000e-09
GCST002971_2	Corticobasal degeneration	1.000000e-12
GCST003784_19	Multiple system atrophy	7.000000e-07
GCST003872_11	QRS complex (12-leadsum)	2.000000e-14
GCST004092_1	Plasma t-tau levels	1.000000e-12
GCST004902_11	Parkinson’s disease	1.000000e-68
GCST005116_48	Male-pattern baldness	1.000000e-24
GCST005116_49	Male-pattern baldness	1.000000e-26
GCST005116_50	Male-pattern baldness	3.000000e-16
GCST005141_26	Cognitive ability (MTAG)	5.000000e-12

EFO canonical traits (35, from GWAS)

EFO ID	Trait name
EFO:0004886	intracranial volume measurement
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0005054	QRS complex
EFO:0007742	QRS amplitude
EFO:0004760	t-tau measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0007660	neuroticism measurement
EFO:0008393	reaction time measurement
EFO:0009458	alcohol use disorder measurement
EFO:0008475	mood instability measurement
EFO:0009599	feeling emotionally hurt measurement
EFO:0009938	Anilide use measurement
EFO:0009902	handedness
EFO:0004363	information processing speed
EFO:0009695	household income
EFO:0010698	retinal break
EFO:0004509	hemoglobin measurement
EFO:0004641	white matter integrity
EFO:0008111	diet measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0004918	age at diagnosis
EFO:0005670	smoking initiation
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0010701	mean reticulocyte volume
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D000544	Alzheimer Disease	C10.228.140.380.100; C10.574.945.249; F03.615.400.100
D003704	Dementia	C10.228.140.380; F03.615.400
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D019578	Multiple System Atrophy	C10.177.575.550; C10.228.140.079.612; C10.228.662.550; C10.574.928.625
D020734	Parkinsonian Disorders	C10.228.140.079.862; C10.228.662.600
D020774	Pick Disease of the Brain	C10.228.140.380.266.299.500; F03.615.400.380.299.500
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C537240	Progressive supranuclear palsy atypical (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL1293224 (SINGLE PROTEIN), CHEMBL4296122 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296123 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296124 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066025 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193767 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

449 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 934,933 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL101	PHENYLBUTAZONE	4	59,455
CHEMBL1010	CEFOTAXIME SODIUM	4	4,928
CHEMBL1018	DIENESTROL	4	5,607
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1042	CHOLECALCIFEROL	4	64,162
CHEMBL1051	LATANOPROST	4	14,975
CHEMBL1055	CHLORTHALIDONE	4	20,442
CHEMBL1057	FLUORESCEIN	4	329,940
CHEMBL1068	OXCARBAZEPINE	4	16,118
CHEMBL1070	NABUMETONE	4	55,063
CHEMBL1073	GLIPIZIDE	4	42,268
CHEMBL1083993	AMIODARONE HYDROCHLORIDE	4	3,265
CHEMBL1086440	TRICLABENDAZOLE	4	4,136
CHEMBL1088	MESORIDAZINE	4	12,814
CHEMBL1091250	INDIGOTINDISULFONATE	4	340
CHEMBL1092	TRIHEXYPHENIDYL HYDROCHLORIDE	4	7,793
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1103	FURAZOLIDONE	4	14,492
CHEMBL1108	DROPERIDOL	4
CHEMBL1112	ARIPIPRAZOLE	4
CHEMBL1116	RALOXIFENE HYDROCHLORIDE	4
CHEMBL1117	IDARUBICIN	4
CHEMBL112	ACETAMINOPHEN	4
CHEMBL1131	ACITRETIN	4
CHEMBL11359	CISPLATIN	4
CHEMBL1159650	CLOBETASOL PROPIONATE	4
CHEMBL1169	AMINOSALICYLIC ACID	4
CHEMBL117785	TETRABENAZINE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1800547	MAPT		0.00	0
rs9468	MAPT		0.00	0
rs1052587	MAPT		0.00	0
rs1001945	MAPT		0.00	0
rs11867549	MAPT		0.00	0
rs1467967	MAPT		0.00	0
rs242557	MAPT		0.00	0
rs2435207	MAPT		0.00	0
rs3785883	MAPT		0.00	0
rs8079215	MAPT		0.00	0
rs919463	MAPT		0.00	0
rs7521	KANSL1, MAPT		0.00	0

Binding affinities (BindingDB)

145 measured of 205 human assays (234 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
7-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-amine	KI	0.18 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.22 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	0.224 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-7-amine	KI	0.29 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-methoxy-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.29 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
8-methoxy-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.32 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N-methyl-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-amine	KI	0.33 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-8-amine	KI	0.33 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-7-amine	KI	0.383 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	0.4 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-(2-fluoroethoxy)-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.41 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-amine	KI	0.423 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-(fluoromethoxy)-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.43 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	0.43 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	0.438 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-(1H-pyrrolo[2,3-c]pyridin-5-yl)pyrrolo[2,3-c]pyridine	KI	0.48 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-ol	KI	0.48 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
5-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-7-amine	KI	0.494 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-8-amine	KI	0.512 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-7-ol	KI	0.53 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N-methyl-4-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	0.53 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.54 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
4-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	0.55 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-methyl-5-pyrrolo[2,3-c]pyridin-1-ylpyrrolo[2,3-c]pyridine	KI	0.62 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-ol	KI	0.67 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-8-amine	KI	0.672 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
8-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-7-amine	KI	0.677 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N-methyl-5-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	0.69 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	0.75 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-(5-ethynyl-4-methyl-2-pyridinyl)pyrrolo[2,3-c]pyridine	KI	0.75 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N-methyl-3-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)aniline	KI	0.76 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
8-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-amine	KI	0.784 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-[5-(3-fluoroprop-1-ynyl)-4-methyl-2-pyridinyl]pyrrolo[2,3-c]pyridine	KI	0.87 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N,N-dimethyl-5-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	0.96 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-(5-prop-1-ynyl-2-pyridinyl)pyrrolo[2,3-c]pyridine	KI	0.98 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
5-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)-1,3-thiazole	KI	1.02 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
5-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	1.05 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
5-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	1.06 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-8-amine	KI	1.07 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
5-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-6-amine	KI	1.09 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-[5-(2-fluoro-4-pyridinyl)-2-pyridinyl]pyrrolo[2,3-c]pyridine	KI	1.13 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-[5-(1H-pyrazol-5-yl)-2-pyridinyl]pyrrolo[2,3-c]pyridine	KI	1.13 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
8-(fluoromethoxy)-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	1.14 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-(5-pyridin-2-yl-2-pyridinyl)pyrrolo[2,3-c]pyridine	KI	1.14 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-8-ol	KI	1.16 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
7-iodo-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	1.17 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
6-(fluoromethoxy)-3-pyrrolo[2,3-c]pyridin-1-ylisoquinoline	KI	1.23 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
8-fluoro-3-pyrrolo[2,3-c]pyridin-1-ylisoquinolin-5-amine	KI	1.28 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
1-[5-(1-methylpyrazol-4-yl)-2-pyridinyl]pyrrolo[2,3-c]pyridine	KI	1.32 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles
N-ethyl-4-(6-pyrrolo[2,3-c]pyridin-1-yl-3-pyridinyl)pyridin-2-amine	KI	1.4 nM	US-10022461: Pyrrolo[2,3-C]pyridines as imaging agents for neurofibrilary tangles

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.89	Kd	0.13	nM	CHEMBL6001659
9.74	Ki	0.18	nM	CHEMBL5957723
9.66	Ki	0.22	nM	CHEMBL5768771
9.65	Ki	0.224	nM	CHEMBL6002646
9.54	Ki	0.29	nM	CHEMBL6021213
9.54	Ki	0.29	nM	CHEMBL5863707
9.49	Ki	0.32	nM	CHEMBL5975228
9.48	Ki	0.33	nM	CHEMBL5987114
9.48	Ki	0.33	nM	CHEMBL5880502
9.42	Ki	0.383	nM	CHEMBL5973966
9.40	IC50	0.4	nM	CHEMBL5278104
9.40	Ki	0.4	nM	CHEMBL5797835
9.39	Ki	0.41	nM	CHEMBL5937022
9.37	Ki	0.43	nM	CHEMBL5839922
9.37	Ki	0.43	nM	FLORQUINITAU
9.37	Ki	0.423	nM	CHEMBL5887511
9.36	Ki	0.438	nM	CHEMBL6054902
9.36	Kd	0.44	nM	CHEMBL5771524
9.34	Ki	0.46	nM	CHEMBL5265782
9.32	Ki	0.48	nM	CHEMBL2036430
9.32	Ki	0.48	nM	CHEMBL5938996
9.32	Ki	0.48	nM	CHEMBL5927890
9.31	Ki	0.494	nM	CHEMBL5825341
9.31	Kd	0.49	nM	CHEMBL6035240
9.29	Ki	0.512	nM	CHEMBL5822831
9.28	Ki	0.53	nM	CHEMBL5885785
9.28	Ki	0.53	nM	CHEMBL5973641
9.27	Ki	0.54	nM	CHEMBL6054703
9.26	Ki	0.55	nM	CHEMBL5897281
9.21	Ki	0.62	nM	CHEMBL5824217
9.17	Ki	0.67	nM	CHEMBL5963473
9.17	Ki	0.677	nM	CHEMBL6010620
9.17	Ki	0.672	nM	CHEMBL5784414
9.16	Ki	0.69	nM	CHEMBL5979548
9.15	Kd	0.7	nM	CHEMBL2203439
9.12	Ki	0.75	nM	CHEMBL6056202
9.12	Ki	0.75	nM	CHEMBL5995493
9.12	Ki	0.76	nM	CHEMBL5922760
9.11	Ki	0.784	nM	CHEMBL5818749
9.06	Ki	0.87	nM	CHEMBL5930983
9.02	Ki	0.96	nM	CHEMBL5972775
9.01	Ki	0.98	nM	CHEMBL5955694
9.01	Kd	0.97	nM	CHEMBL6034599
9.00	IC50	1	nM	CHEMBL3286988
8.99	Ki	1.02	nM	CHEMBL5906082
8.98	Ki	1.05	nM	CHEMBL5826830
8.97	Ki	1.06	nM	CHEMBL5961815
8.97	Ki	1.07	nM	CHEMBL5947052
8.96	Ki	1.09	nM	CHEMBL5977182
8.95	Ki	1.13	nM	CHEMBL5749573

PubChem BioAssay actives

337 with measured affinity, of 870 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(cyclopropanecarbonylamino)-N-[4-(3,3-dimethylmorpholin-4-yl)-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0004	uM
4-[[4-(6-methoxy-1,3-benzothiazol-2-yl)triazol-1-yl]methyl]benzonitrile	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0005	uM
4-[(6-iodo-1,3-benzothiazol-2-yl)diazenyl]-N,N-dimethylaniline	663425: Displacement of Thioflavin S from recombinant human tau expressed in Escherichia coli after 30 mins by fluorescence assay	ki	0.0005	uM
1-(111C)methyl-2-[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methylsulfinyl]benzimidazole	712328: Binding affinity to heparin induced human Tau 441 at 50 pM to 500 nM after 30 mins	kd	0.0007	uM
(2Z)-6-(3-chlorophenyl)-2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0010	uM
4-[(E)-2-(1-butyl-3,3-dimethylindol-1-ium-2-yl)ethenyl]-N,N-diethylaniline iodide	718586: Displacement of thiazine red R from human Tau aggregate expressed in Escherichia coli after 30 mins by fluorimetric analysis	ic50	0.0014	uM
2-[(3-chlorocyclobutanecarbonyl)amino]-N-[4-(4,4-difluoropiperidin-1-yl)-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0017	uM
2-(cyclopropanecarbonylamino)-N-[4-[(3S)-3-methylmorpholin-4-yl]-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0020	uM
4-[(1E,3E)-4-[6-[(1E,3E)-4-[4-(dimethylamino)phenyl]buta-1,3-dienyl]pyrimidin-4-yl]buta-1,3-dienyl]-N,N-dimethylaniline	706436: Displacement of thiazene red from tau aggregate	ic50	0.0020	uM
4,6-bis[(E)-2-(4-pyrrolidin-1-ylphenyl)ethenyl]pyrimidine	706436: Displacement of thiazene red from tau aggregate	ic50	0.0020	uM
(2Z)-6-(4-chlorophenyl)-2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0020	uM
(2Z)-2-[(3-chloro-4-hydroxy-5-methoxyphenyl)methylidene]-6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0020	uM
(2Z)-2-[(3-bromo-4-hydroxy-5-methoxyphenyl)methylidene]-6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0020	uM
[4-(trifluoromethyl)phenyl]methyl 6-methoxy-1,3-benzothiazole-2-carboxylate	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0024	uM
Lansoprazole	712328: Binding affinity to heparin induced human Tau 441 at 50 pM to 500 nM after 30 mins	ki	0.0025	uM
2-(cyclopropanecarbonylamino)-N-[4-(2-hydroxypropan-2-yl)-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0028	uM
(2Z)-2-[(3-chloro-4-hydroxy-5-methoxyphenyl)methylidene]-6-[3-(trifluoromethyl)phenyl]imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0030	uM
7-(2-fluoro-4-pyridinyl)-5H-pyrido[4,3-b]indole	1831371: Displacement of [3H]PI-2620 from Tau in human brain homogenate incubated for 60 mins by radioligand binding assay	ic50	0.0031	uM
7-(2-fluoro-3-pyridinyl)-5H-pyrido[4,3-b]indole	1831371: Displacement of [3H]PI-2620 from Tau in human brain homogenate incubated for 60 mins by radioligand binding assay	ic50	0.0035	uM
2-[1-[(4-fluorophenyl)methyl]triazol-4-yl]-6-methoxy-1,3-benzothiazole	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0038	uM
4-[(E)-2-[6-[(E)-2-[4-(dimethylamino)phenyl]ethenyl]pyrimidin-4-yl]ethenyl]-N,N-dimethylaniline	706436: Displacement of thiazene red from tau aggregate	ic50	0.0040	uM
11-(2-fluoro-4-pyridinyl)-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	1831371: Displacement of [3H]PI-2620 from Tau in human brain homogenate incubated for 60 mins by radioligand binding assay	ic50	0.0049	uM
2-(cyclopropanecarbonylamino)-N-[4-(4,4-difluoropiperidin-1-yl)-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0050	uM
(2Z)-6-(4-chlorophenyl)-2-[(3,4-dihydroxy-5-methoxyphenyl)methylidene]imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0050	uM
(2Z)-2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]-6-pyridin-4-ylimidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0050	uM
1,3,3-trimethyl-2-[(E)-2-(4-pyrrolidin-1-ylphenyl)ethenyl]indol-1-ium iodide	718586: Displacement of thiazine red R from human Tau aggregate expressed in Escherichia coli after 30 mins by fluorimetric analysis	ic50	0.0051	uM
4-[4-[(E)-2-[5-[(E)-2-(4-morpholin-4-ylphenyl)ethenyl]pyrazin-2-yl]ethenyl]phenyl]morpholine	706436: Displacement of thiazene red from tau aggregate	ic50	0.0060	uM
5-[4-(6-methoxy-1,3-benzothiazol-2-yl)triazol-1-yl]pyridin-2-amine	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0063	uM
(2Z)-2-[(4-hydroxy-3,5-dimethoxyphenyl)methylidene]-6-(3-methyl-4-pyridinyl)imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0080	uM
2-[1-[6-(methylamino)-3-pyridinyl]triazol-4-yl]-1,3-benzothiazol-6-ol	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0081	uM
N-[4-(2-methylmorpholin-4-yl)-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1934091: Inhibition of Tau (unknown origin) phosphorylation	ic50	0.0092	uM
N-[4-[(2S)-2-methylmorpholin-4-yl]-3-pyridinyl]-2-phenylimidazo[1,2-b]pyridazine-8-carboxamide	1948327: Inhibition of tau 4R1N phosphorylation (unknown origin) at S396 residue transfected in human U2OS cells coexpressing GFP-tagged beta catenin incubated overnight by high content imaging assay	ic50	0.0092	uM
2-(4-cyanoanilino)-N-[4-(4-fluorophenyl)-3-pyridinyl]pyrimidine-4-carboxamide	2091851: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0100	uM
2-(cyclopropanecarbonylamino)-N-[4-[(3R)-3-methylmorpholin-4-yl]-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0120	uM
2-(4-cyanoanilino)-N-(4-phenyl-3-pyridinyl)pyrimidine-4-carboxamide	2091851: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0120	uM
2,5-bis[(E)-2-(4-methoxyphenyl)ethenyl]pyrazine	706436: Displacement of thiazene red from tau aggregate	ic50	0.0130	uM
4-[[6-[2-[2-(2-fluoroethoxy)ethoxy]ethoxy]-1,3-benzothiazol-2-yl]diazenyl]-N,N-dimethylaniline	663425: Displacement of Thioflavin S from recombinant human tau expressed in Escherichia coli after 30 mins by fluorescence assay	ki	0.0130	uM
(2Z)-2-[(3-fluoro-4-hydroxy-5-methoxyphenyl)methylidene]-6-[3-(trifluoromethoxy)phenyl]imidazo[2,1-b][1,3]thiazol-3-one	1156051: Inhibition of recombinant human microtubule associated protein tau aggregation by Thiazin-red R displacement fluorescence assay	ic50	0.0130	uM
(3-fluorophenyl)methyl 6-methoxy-1,3-benzothiazole-2-carboxylate	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0132	uM
2-[2-[4-(6-methoxy-1,3-benzothiazol-2-yl)triazol-1-yl]ethoxy]ethanol	1956626: Displacement of [11C]PBB3 in human brain tau incubated for 30 mins by radioligand binding assay	ki	0.0136	uM
2-[(3-chlorocyclobutanecarbonyl)amino]-N-[4-(4-chlorophenyl)-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0150	uM
11-(2-fluoro-3-pyridinyl)-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaene	1831371: Displacement of [3H]PI-2620 from Tau in human brain homogenate incubated for 60 mins by radioligand binding assay	ic50	0.0155	uM
(2Z)-2-[[4-(dimethylamino)phenyl]methylidene]-5-iodo-1H-indol-3-one	677224: Binding affinity to human Tau aggregates after 30 mins by Thioflavin-S-based fluorescence assay	ki	0.0170	uM
4,6-bis[(E)-2-(4-piperidin-1-ylphenyl)ethenyl]pyrimidine	706436: Displacement of thiazene red from tau aggregate	ic50	0.0170	uM
2-(cyclopropanecarbonylamino)-N-[4-[(2S)-2-methylmorpholin-4-yl]-3-pyridinyl]pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0180	uM
4-(2-fluoro-4-pyridinyl)-3-thia-5,7,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,9,11-pentaene	1831371: Displacement of [3H]PI-2620 from Tau in human brain homogenate incubated for 60 mins by radioligand binding assay	ic50	0.0180	uM
N-[4-(3-hydroxy-3-methylbutoxy)-3-pyridinyl]-2-(2-methylpropanoylamino)pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0190	uM
2-(cyclopropanecarbonylamino)-N-(4-morpholin-4-yl-3-pyridinyl)pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0230	uM
2-(cyclopropanecarbonylamino)-N-(4-piperidin-1-yl-3-pyridinyl)pyridine-4-carboxamide	1937604: Inhibition of tau phosphorylation (unknown origin)	ic50	0.0230	uM
N-[2-(5-chloro-1H-indol-3-yl)ethyl]-4-(3-cyanophenyl)benzamide	692864: Inhibition of Tau phosphorylation by cell based assay	ec50	0.0240	uM

CTD chemical–gene interactions

180 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, increases methylation, affects cotreatment	9
Tretinoin	affects localization, affects binding, decreases expression, affects reaction, increases expression (+4 more)	7
Benzo(a)pyrene	affects methylation, decreases expression	4
Aflatoxin B1	affects expression, decreases expression, increases methylation	4
Aluminum Hydroxide	increases expression, increases reaction, affects cotreatment, decreases reaction	3
Estradiol	increases expression, increases phosphorylation, decreases reaction	3
Hydrogen Peroxide	decreases expression, decreases reaction, increases reaction, increases expression, increases phosphorylation	3
Methamphetamine	affects reaction, increases phosphorylation, increases expression, decreases reaction	3
Nickel	increases response to substance, decreases expression, increases expression, increases phosphorylation	3
Okadaic Acid	increases activity, increases phosphorylation, decreases activity, affects cotreatment, affects binding (+1 more)	3
bisphenol A	decreases expression, decreases methylation, increases methylation	2
annonacin	increases reaction, increases expression, increases phosphorylation, increases splicing, increases response to substance	2
cyanoginosin LR	increases phosphorylation, decreases reaction	2
SB 203580	decreases reaction, increases phosphorylation	2
dorsomorphin	affects cotreatment, increases expression, decreases cleavage, decreases expression, decreases reaction	2
Acetylcysteine	increases phosphorylation, increases abundance, increases expression, decreases reaction	2
Air Pollutants	decreases expression, increases abundance, increases phosphorylation, increases reaction, decreases reaction (+1 more)	2
Arsenic	affects methylation, affects expression	2
Cadmium	decreases expression, increases expression, decreases reaction	2
Copper	decreases reaction, decreases abundance, affects binding, decreases phosphorylation, increases phosphorylation	2
Doxorubicin	affects response to substance, decreases expression, affects cotreatment	2
Formaldehyde	affects binding, affects reaction, increases reaction	2
Heparin	increases reaction, affects binding	2
Mercuric Chloride	affects folding, increases reaction, decreases reaction, increases phosphorylation, affects binding	2
Methylene Blue	decreases expression, decreases phosphorylation, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression	2
Paclitaxel	affects cotreatment, affects response to substance, decreases expression	2
Acrylamide	affects binding, increases reaction, increases expression, increases phosphorylation	2
Particulate Matter	increases phosphorylation, increases reaction, decreases reaction, increases expression, decreases expression (+1 more)	2

ChEMBL screening assays

184 unique, capped per target: 180 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1613828	Binding	PUBCHEM_BIOASSAY: Tau ThS binding assay. (Class of assay: confirmatory) [Related pubchem assays: 596 ]	PubChem BioAssay data set
CHEMBL1613899	Functional	PUBCHEM_BIOASSAY: Confirmation Concentration-Response Assay for Inhibitors of Tau Fibril Formation, Total Fluorescence Counterscreen for Fluorescence Polarization. (Class of assay: confirmatory) [Related pubchem assays: 1463 ]	PubChem BioAssay data set

Cellosaurus cell lines

133 cell lines: 96 induced pluripotent stem cell, 21 finite cell line, 7 transformed cell line, 5 cancer cell line, 3 spontaneously immortalized cell line, 1 conditionally immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_9S56	UCLi003-A	Induced pluripotent stem cell	Female
CVCL_A4GA	H236 C6 GC	Induced pluripotent stem cell	Female
CVCL_A4MZ	MAPT N279K-1	Induced pluripotent stem cell	Male
CVCL_A4NA	MAPT N279K-2	Induced pluripotent stem cell	Female
CVCL_A7GT	SIGi001-A-16	Induced pluripotent stem cell	Female
CVCL_A9Q6	UCLi003-B	Induced pluripotent stem cell	Female
CVCL_A9R2	FTDP-17-1-I	Induced pluripotent stem cell	Male
CVCL_A9R3	FTDP-17-1-II	Induced pluripotent stem cell	Male
CVCL_A9R4	FTDP-17-2-I	Induced pluripotent stem cell	Female
CVCL_A9R5	FTDP-17-2-II	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

189 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT00376051	PHASE4	COMPLETED	Serotonergic Function and Behavioural and Psychological Symptoms of Frontotemporal Dementia
NCT00545974	PHASE4	COMPLETED	Memantine (10mg BID) for the Frontal and Temporal Subtypes of Frontotemporal Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT06093126	PHASE4	RECRUITING	Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT00594737	PHASE3	COMPLETED	Open Label Pilot Study of the Effects of Memantine on FDG-PET in Frontotemporal Dementia
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT04374136	PHASE3	TERMINATED	A Phase 3 Study to Evaluate Efficacy and Safety of AL001 in Frontotemporal Dementia (INFRONT-3)
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT00416169	PHASE2	COMPLETED	A Pilot Study to Explore the Safety and Tolerability of Galantamine HBr in the Treatment of Pick Complex/Frontotemporal Dementia
NCT01890343	PHASE2	COMPLETED	Imaging Characteristics of Florbetapir 18F in Patients With Frontotemporal Dementia, Alzheimer’s Disease and Normal Controls.
NCT01937013	PHASE2	COMPLETED	Impact of Emotional Mimicry and Oxytocin on Frontotemporal Dementia
NCT02676843	PHASE2	COMPLETED	Tau PET Imaging With 18F-AV-1451 in Subjects With MAPT Mutations
NCT02862210	PHASE2	COMPLETED	Low-Dose Lithium for the Treatment of Behavioral Symptoms in Frontotemporal Dementia
NCT03260920	PHASE2	UNKNOWN	Intranasal Oxytocin for Frontotemporal Dementia
NCT03987295	PHASE2	COMPLETED	A Phase 2 Study to Evaluate Safety of Long-term AL001 Dosing in Frontotemporal Dementia (FTD) Patients (INFRONT-2)
NCT04220021	PHASE2	ACTIVE_NOT_RECRUITING	Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD
NCT04489017	PHASE2	COMPLETED	Palmitoylethanolamide Combined With Luteoline in Frontotemporal Dementia Patients. A Randomized Controlled Trial
NCT04993755	PHASE2	COMPLETED	A Phase 2a Study of TPN-101 in Patients With C9ORF72 ALS/FTD
NCT05742698	PHASE2	RECRUITING	Nabilone for Agitation in Frontotemporal Dementia
NCT06604520	PHASE2	RECRUITING	Vortioxetine for the Treatment of Mood and Cognitive Symptoms in Frontotemporal Dementia
NCT07154485	PHASE2	NOT_YET_RECRUITING	Investigator Initiated Study for the Safety and Efficacy in Frontotemporal Dementia
NCT00139373	PHASE2	UNKNOWN	Study of the Distractibility Syndrome in Patients With Progressive Supranuclear Palsy
NCT03068468	PHASE2	TERMINATED	Study of BIIB092 in Participants With Progressive Supranuclear Palsy
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT00077896	PHASE1	COMPLETED	Direct Current Brain Polarization in Frontotemporal Dementia
NCT00674960	PHASE1	UNKNOWN	Far Infrared Irradiation for the Management, Control and Treatment of Frontotemporal Dementia
NCT01386333	PHASE1	COMPLETED	Safety Study of Intranasal Oxytocin in Frontotemporal Dementia
NCT01623284	PHASE1	COMPLETED	PiB PET Scanning in Speech and Language Based Dementias
NCT03040713	PHASE1	COMPLETED	Flortaucipir PET Imaging in Subjects With FTD
NCT03636204	PHASE1	COMPLETED	A First in Human Study in Healthy Volunteers and in Participants With Frontotemporal Dementia With Granulin (GRN) Mutation
NCT05184569	PHASE1	RECRUITING	Veri-T: A Trial of Verdiperstat in Patients With svPPA Due to TDP-43 Pathology
NCT05315661	PHASE1	ACTIVE_NOT_RECRUITING	The Safety and The Efficacy Evaluation of ET-STEM in Patients With Frontotemporal Dementia
NCT06226064	PHASE1	COMPLETED	A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001 in Healthy Participants
NCT06705192	PHASE1	COMPLETED	Study in Asymptomatic GRN-FTD Patients to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VES001
NCT02658916	PHASE1	TERMINATED	Extension Study of BIIB092 in Participants With Progressive Supranuclear Palsy (PSP) Who Participated in CN002003