Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin, a component of the presenilin protein complex

M. Nishimura, G. Yu, G. Levesque, D. M. Zhang, L. Ruel, F. Chen, P. Milman, E. Holmes, Y. Liang, T. Kawakai, E. Jo, A. Supala, E. Rogaeva, D. M. Xu, C. Janus, L. Levesque, Q. Bi, M. Duthie, R. Rozmahel, K. MattilaL. Lannfelt, D. Westaway, H. T J Mount, J. Woodgett, P. E. Fraser, P. St. George-Hyslop

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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.

Original languageEnglish (US)
Pages (from-to)164-169
Number of pages6
JournalNature medicine
Volume5
Issue number2
DOIs
StatePublished - Feb 1 1999

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nishimura, M., Yu, G., Levesque, G., Zhang, D. M., Ruel, L., Chen, F., Milman, P., Holmes, E., Liang, Y., Kawakai, T., Jo, E., Supala, A., Rogaeva, E., Xu, D. M., Janus, C., Levesque, L., Bi, Q., Duthie, M., Rozmahel, R., ... St. George-Hyslop, P. (1999). Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin, a component of the presenilin protein complex. Nature medicine, 5(2), 164-169. https://doi.org/10.1038/5526