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Presenilin 1 Binding Proteins and Their Function
Laboratory for Alzheimer's Disease |
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It has been reported that the presenilin 1 (PS1) mutations affect the APP metabolism and increase the production of Ab42. To understand the pathological roles of mutant PS1, we investigated the proteins that interact with PS1 using PS1 antibodies we developed. We have identified that glycogen synthase kinase-3b(GSK-3b), tau and b-catenin from human brain samples and cultured cells interact with PS1, as the proteins co-immunoprecipitating with PS1.
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PS1 may act as a molecular tether, connecting GSK-3B with important substrates.
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We have also clarified that the function domain of interaction between PS 1 and GSK-3b and tau proteins occurs at PS1 amino acid part 250-298 and that of b-catenin occurs at PS1 amino acid part 322-450.
The mutant PS1 does not show the different affinity with the tau or b-catenin but increases the affinity with GSK-3b. Tau and b-catenin are the substrates of GSK-3b. The expression of mutant PS1 in cell lines has resulted in the promotion of phosphorylation of the tau by GSK-3b. In addition, we have shown that the amount of b-catenin adjusted by the activity of GSK-3b in the soluble portion decreases as a result of the expression of PS1 mutations in cell lines. In other words, it seems that the PS1 plays the role in linking GSK-3b with its substrates. Our results suggest that the PS1/GSK-3b complex plays a specific role in the increase in the Ab42 production.
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Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M., Yamaguchi, H., Sugihara, S., Wolozin, B. Presenilin 1 associates with glycogen synthase kinase-3b and its substrate tau.
Proc. Natl. Acad. Sci. USA. 95, 9637-9641(1998).
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Murayama, M., Tanaka, S., Palatino, J., Murayama, O., Honda, T., Nihonmatsu, N., Wolozin, B., Takashima, A. Direct association of presenilin-1 with b-catenin.
FEBS lett. 433, 73-77(1998).
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