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)

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

To elucidate involvement of tau protein in neurodegenerative processes in Alzheimer disease and related disorders, self-assembly process and degradative process of tau protein were examined. To understand the mechanisms of the aggregation, binding affinity of tau protein to 14-3-3 protein, which converts tau to a filamentous or aggregated form. was investigated employing a surface plasmon resonance assay. Phosphorylation of tau by protein kinase A increased affinity of tau to 14-3-3, whereas the phosphorylation attenuated formation of filaments or aggregates. FTDP-17 mutation increased affinity of unphosphorlated tau to 14-3-3, compared to wild typed unphosphorylated tau. However the phosphorylation increased its affinity further to the similar level of the affinity of phosphorylated wild typed tau. Similarly the phosphorylation also attenuated formation of filaments or aggreeagates from FTDP-17 mutated tau. To understand the mechanisms of the intracellular accumulation, possible involvement of proteases were studied. Among several proteases, puromycin-sensitive aminopeptidase (PSA) was found as a predominant regulator of degradation of tau protein. In addition FTDP-17 mutation increased phosphorylation of tau proten in cells, and attenuated intracellular degradation of tau protein. These results suggest that self-assembly and accumulation of tau protein are regulated by phosphorylation, and FTDP-17 mutation affects those complexed processes.
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PMID:[Alzheimer disease and tau protein]. 2319 53