Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tau-tubulin kinase-1 (TTBK1) is involved in phosphorylation of tau protein at specific Serine/Threonine residues found in paired helical filaments, suggesting its role in tauopathy pathogenesis. We found that TTBK1 levels were upregulated in brains of human Alzheimer' disease (AD) patients compared with age-matched non-AD controls. To understand the effects of TTBK1 activation in vivo, we developed transgenic mice harboring human full-length TTBK1 genomic DNA (TTBK1-Tg). Transgenic TTBK1 is highly expressed in subiculum and cortical pyramidal layers, and induces phosphorylated neurofilament aggregation. TTBK1-Tg mice show significant age-dependent memory impairment as determined by radial arm water maze test, which is associated with enhancement of tau and neurofilament phosphorylation, increased levels of p25 and p35, both activators of cyclin-dependent protein kinase 5 (CDK5), enhanced calpain I activity, and reduced levels of hippocampal NMDA receptor types 2B (NR2B) and D. Enhanced CDK5/p35 complex formation is strongly correlated with dissociation of F-actin from p35, suggesting the inhibitory mechanism of CDK5/p35 complex formation by F-actin. Expression of recombinant TTBK1 in primary mouse cortical neurons significantly downregulated NR2B in a CDK5- and calpain-dependent manner. These data suggest that TTBK1 in AD brain may be one of the underlying mechanisms inducing CDK5 and calpain activation, NR2B downregulation, and subsequent memory dysfunction.
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PMID:Spatial learning impairment, enhanced CDK5/p35 activity, and downregulation of NMDA receptor expression in transgenic mice expressing tau-tubulin kinase 1. 1911 86

Neurofibrillary tangles, one of the characteristic neuropathological lesions found in Alzheimer's disease (AD) brains, are composed of abnormally hyperphosphorylated tau protein. Tau-tubulin kinase-1 (TTBK1) is a brain-specific protein kinase involved in tau phosphorylation at AD-related sites. We examined genetic variations of TTBK1 by genotyping nine haplotype tagging SNPs (htSNPs) (rs2104142, rs2651206, rs10807287, rs7764257, rs3800294, rs1995300, rs2756173, rs6936397, and rs6458330) in a group of 645 Spanish late-onset AD patients and 738 healthy controls. Using a recessive genetic model, minor allele homozygotes for rs2651206 in intron 1 (OR=0.50, p=0.0003), rs10807287 in intron 5 (OR=0.49, p=0.0002), and rs7764257 in intron 9 (OR=0.57, p=0.023), which are in strong linkage disequilibrium, had a lower risk of developing AD than subjects homozygotes and heterozygotes for the major allele. TTBK1 is a promising new candidate tau phosphorylation-related gene for AD risk.
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PMID:Genetic variations in tau-tubulin kinase-1 are linked to Alzheimer's disease in a Spanish case-control cohort. 2009 81

Tau-tubulin kinase-1 (TTBK1) phosphorylates microtubule-associated protein tau at specific serine/threonine residues found in paired helical filaments (PHFs), and its expression is up-regulated in the brain in Alzheimer disease, suggesting its role in tauopathy pathogenesis. To understand the effects of TTBK1 on tauopathy in vivo, we have developed bigenic mice overexpressing full-length TTBK1 and the P301L tau mutant. The bigenic mice show enhanced tau phosphorylation at multiple sites (AT8, 12E8, PHF-1, and pS422), tauC3-immunoreactive tau fragmentation, and accumulation of tau aggregates in cortical and hippocampal neurons at 12-13 mo of age. However, the phosphorylated tau aggregates were predominantly sarkosyl soluble and migrated in the light sucrose density fraction after discontinuous sucrose gradient ultracentrifugation, which suggests that they form small oligomers. The bigenic mice show significant locomotor dysfunction as determined by both rotorod and grip strength tests, as well as enhanced loss of motor neurons in the L4-L5 spinal cord. This neuronal dysfunction and degeneration was associated with increased levels of tau oligomers, cyclin-dependent protein kinase 5 activators p35 and p25, and pY216 phosphorylated glycogen synthase kinase 3-beta. These data suggest that TTBK1 up-regulation enhances tau phosphorylation and oligomerization, whose toxicity results in enhanced neurodegeneration and locomotor dysfunction in a tauopathy animal model.
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PMID:Tau-tubulin kinase 1 enhances prefibrillar tau aggregation and motor neuron degeneration in P301L FTDP-17 tau-mutant mice. 2035 35

Tau-tubulin kinase-1 (TTBK1) is a central nervous system (CNS)-specific protein kinase implicated in the pathological phosphorylation of tau. TTBK1-transgenic mice show enhanced neuroinflammation in the CNS. Double-transgenic mice expressing TTBK1 and frontotemporal dementia with parkinsonism-17-linked P301L (JNPL3) tau mutant (TTBK1/JNPL3) show increased accumulation of oligomeric tau protein in the CNS and enhanced loss of motor neurons in the ventral horn of the lumbar spinal cord. To determine the role of TTBK1-induced neuroinflammation in tauopathy-related neuropathogenesis, age-matched TTBK1/JNPL3, JNPL3, TTBK1, and non-transgenic littermates were systematically characterized. There was a striking switch in the activation phenotype and population of mononuclear phagocytes (resident microglia and infiltrating macrophages) in the affected spinal cord region: JNPL3 mice showed accumulation of alternatively activated microglia, whereas TTBK1 and TTBK1/JNPL3 mice showed accumulation of classically activated infiltrating peripheral monocytes. In addition, expression of chemokine ligand 2, a chemokine important for the recruitment of peripheral monocytes, was enhanced in TTBK1 and TTBK1/JNPL3 but not in other groups in the spinal cord. Furthermore, primary cultured mouse motor neurons showed axonal degeneration after transient expression of the TTBK1 gene or treatment with conditioned media derived from lipopolysaccharide-stimulated microglia; this was partially blocked by silencing of the endogenous TTBK1 gene in neurons. These data suggest that TTBK1 accelerates motor neuron neurodegeneration by recruiting proinflammatory monocytes and enhancing sensitivity to neurotoxicity in inflammatory conditions.
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PMID:Accelerated neurodegeneration and neuroinflammation in transgenic mice expressing P301L tau mutant and tau-tubulin kinase 1. 2441 58

Tau-tubulin kinase (TTBK) belongs to casein kinase superfamily and phosphorylates microtubule-associated protein tau and tubulin. TTBK has two isoforms, TTBK1 and TTBK2, which contain highly homologous catalytic domains but their non-catalytic domains are distinctly different. TTBK1 is expressed specifically in the central nervous system and is involved in phosphorylation and aggregation of tau. TTBK2 is ubiquitously expressed in multiple tissues and genetically linked to spinocerebellar ataxia type 11. TTBK1 directly phosphorylates tau protein, especially at Ser422, and also activates cycline-dependent kinase 5 in a unique mechanism. TTBK1 protein expression is significantly elevated in Alzheimer's disease (AD) brains, and genetic variations of the TTBK1 gene are associated with late-onset Alzheimer's disease in two cohorts of Chinese and Spanish populations. TTBK1 transgenic mice harboring the entire 55-kilobase genomic sequence of human TTBK1 show progression of tau accumulation, neuroinflammation, and neurodegeneration when crossed with tau mutant mice. Our recent study shows that there is a striking switch in mononuclear phagocyte and activation phenotypes in the anterior horn of the spinal cord from alternatively activated (M2-skewed) microglia in P301L tau mutant mice to pro-inflammatory (M1-skewed) infiltrating peripheral monocytes by crossing the tau mice with TTBK1 transgenic mice. TTBK1 is responsible for mediating M1-activated microglia-induced neurotoxicity, and its overexpression induces axonal degeneration in vitro. These studies suggest that TTBK1 is an important molecule for the inflammatory axonal degeneration, which may be relevant to the pathobiology of tauopathy including AD.
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PMID:Tau-tubulin kinase. 2480 23