Abstract
The presenilin proteins are components of high–molecular–weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain β-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non–pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of β-catenin after activation of the Wnt/β-catenin signal transduction pathway. As with their effect on βAPP processing, the effect of PS1 mutations on trafficking of β-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin–β-catenin protein complexes is central to this process.
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Acknowledgements
This work was supported by grants from the Medical Research Council of Canada, Alzheimer Association of Ontario, EJLB Foundation, Howard Hughes Medical Research Foundation, The Canadian Genetic Disease Network, Scottish Rite Charitable Foundation, the Helen B. Hunter Fellowship (G.Y.), the Peterborough–Burgess Fellowship (E.A.R.), and the University of Toronto Department of Medicine Postgraduate Fellowship (M.N.).
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Nishimura, M., Yu, G., Levesque, G. et al. Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin,a component of the presenilin protein complex. Nat Med 5, 164–169 (1999). https://doi.org/10.1038/5526
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DOI: https://doi.org/10.1038/5526
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