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

The serine/threonine kinase glycogen synthase kinase-3beta (GSK-3beta) is expressed in two, alternatively spliced, isoforms: a short form (GSK-3beta1) and a long form containing a 13 amino acid insert in the catalytic domain (GSK-3beta2). We examined the expression of these isoforms in the rat using specific antibodies and found that GSK-3beta2, in contrast to GSK-3beta1, is only expressed in the nervous system. The highest levels of GSK-3beta2 are found in the developing nervous system but expression persists into adulthood. In the adult central nervous system the highest expression of GSK-3beta2 occurs in regions with a high proportion of white matter, suggesting that GSK-3beta2 is expressed in axons. Consistent with this finding, sub-cellular fractionation of neonatal rat brain showed that GSK-3beta2 is present in fractions enriched in neurites and growth cones. Furthermore, we found that when we separated neuronal cell bodies from neurites by culturing embryonic cortical neurons in neurite outgrowth inserts, GSK-3beta2 was present in both compartments. Finally, a rabbit polyclonal antibody raised to the 13 amino acid insert of GSK-3beta2 (anti-8A) that specifically recognises GSK-3beta2, labels the cell body, including the nucleus, neurites and growth cones of embryonic neurons in culture. To compare functionally the two isoforms, we performed in vitro kinase assays. These showed that GSK-3beta1 is more efficient at phosphorylating the microtubule-associated protein MAP1B than GSK-3beta2, consistent with previous findings with the microtubule-associated protein tau. However, when co-expressed with MAP1B in COS-7 cells, both GSK-3beta isoforms equally efficiently phosphorylated MAP1B and had a similar influence on the regulation of microtubule dynamics by MAP1B in these cells. We conclude that the alternatively spliced isoform of GSK-3beta, GSK-3beta2, is neuron-specific and has overlapping activities with GSK-3beta1.
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PMID:An alternatively spliced form of glycogen synthase kinase-3beta is targeted to growing neurites and growth cones. 1960 22

The hallmark of Alzheimer's disease is the pathological aggregation of tau proteins into paired helical filaments and neurofibrillary tangles. This paper evaluates the abnormal expression and localization of chimeric tau molecules at the plasma membrane of COS-7 cells and its relationship with tau polymerization. Overexpression of these proteins, in combination with either tau441 or tau391, induces tau to assemble into beta-pleated sheets that are recognized by Thiazin red. Immunoelectromicroscopy analysis revealed the presence of filaments close to the plasma membrane resembling those found in Alzheimer's disease. The capacity of plasma membrane-associated chimeric tau proteins to capture full length tau was increased in the presence of H(2)O(2) or okadaic acid treatments. This suggests that hyperphosphorylation or an oxidative environment could both influence the biochemical properties of the cell that lead to assembly of paired helical filaments. The altered localization of tau protein at the plasma membrane could play a key role in the assembly of pathological tau.
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PMID:Pathological-like assembly of tau induced by a paired helical filament core expressed at the plasma membrane. 1974 35

In tauopathies, tau protein is hyperphosphorylated, ubiquitinated, and accumulated in the brain; however, the mechanisms underlying this accumulation remain unclear. To gain an understanding of the role of proteases in the metabolism of tau protein, in the present study we evaluated the effects of protease inhibitors in SH-SY5Y human neuroblastoma cells and COS-7 cells transfected with the tau gene. When cells were treated with 0.1-10 micromol/L of lactacystin and 1.0-20 micromol/L of MG-132 (inhibitors of proteasome), 0.1-10 micromol/L of CA-074Me (a cathepsin inhibitor), and 0.1-2 micromol/L of puromycin (a puromycin-sensitive aminopeptidase (PSA) inhibitor) for up to 24 h, there were no significant changes in tau protein levels. However, pulse-chase experiments demonstrated that the proteolysis of tau protein in SH-SY5Y cells was attenuated following treatment of cells with 200 nmol/L puromycin. Increased tau protein levels were also observed in SH-SY5Y cells treated with short interference (si) RNA to PSA to inhibit the expression of PSA. These data suggest that PSA is a protease that catalyses tau protein predominantly in SH-SY5Y cells. The protein metabolism of tau-containing mutations of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was also investigated using pulse-chase experiments. The results indicate attenuated proteolysis of tau in cells transfected with mutant tau genes after 48 h. Further immunocytochemical analysis and subcellular fractionation experiments revealed that the mutations did not alter the intracellular distribution of tau and suggested that impaired accessibility of tau to PSA is unlikely to account for the attenuated proteolysis of tau protein. Western blotting with phosphorylation-dependent antibodies revealed that phosphorylation levels of tau at Thr(231), Ser(396), and Ser(409) were increased in cells transfected with V337M, R406W, and R406W mutant tau genes, respectively. Together, the data suggest that attenuated proteolysis of FTDP-17 mutant tau may be explained by increased phosphorylation levels, resulting in resistance to proteolysis.
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PMID:Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau. 2037 16

Tau is a microtubule-associated protein that plays an important role in Alzheimer's disease and related tauopathies. Approximately one-half of all cases of Frontotemporal dementia with parkinsonism-17 (FTDP-17) are caused by mutations in the MAPT gene. The N279K mutation is one of the three mutations more prevalent in FTDP-17 cases. Several studies have demonstrated that N279K Tau mutation alters alternative splicing inducing the presence of exon 10. Tau is mainly found in the cytosol of neuronal cells although it has also been localized within the nucleus. Here we demonstrate by biochemical and immunohistochemistry studies in COS-7 cells, that the proportion of mutant N279K Tau increases compared with wild-type at the cell nucleus although cell viability is not affected. These data will provide us with a better outline of the nuclear role of tau protein offering new clues related with this tauopathie.
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PMID:Frontotemporal Dementia-Associated N279K Tau Mutation Localizes at the Nuclear Compartment. 3005 Apr 13


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