Presenilin function: Connections to Alzheimer's disease and signal transduction

Paul E. Fraser, Gang Yu, Lyne Lévesque, Masaki Nishimura, Dun Sheng Yang, Howard T J Mount, David Westaway, Peter H. St George-Hyslop

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Missense mutations in presenilin 1 (PS1) and presenilin 2 (PS2) are associated with early-onset familial Alzheimer's disease which displays an accelerated deposition of amyloid plaques and neurofibrillary tangles. Presenilins are multi-spanning transmembrane proteins which localize primarily to the endoplasmic reticulum and the Golgi compartments. We have previously demonstrated that PS1 exists as a high-molecular-mass complex that is likely to contain several functional ligands. Potential binding proteins were screened by the yeast two-hybrid system using the cytoplasmically orientated PS1 loop domain which was shown to interact strongly with members of the armadillo family of proteins, including β-catenin, p0071 and a novel neuron-specific plakophilin-related armadillo protein (NPRAP). Armadillo proteins can have dual functions that encompass the stabilization of cellular junctions/synapses and the mediation of signal transduction pathways. Our observations suggest that PS1 may contribute to both aspects of armadillo-related pathways involving neurite outgrowth and nuclear translocation of β-catenin upon activation of the wingless (Wnt) pathway. Alzheimer's disease (AD)-related presenilin mutations exhibit a dominant gain of aberrant function resulting in the prevention of β-catenin translocation following Wnt signalling. These findings indicate a functional role for PS1 in signalling and suggest that mistrafficking of selected presenilin ligands may be a potential mechanism in the genesis of AD.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalBiochemical Society Symposium
Volume67
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Biochemistry

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    Fraser, P. E., Yu, G., Lévesque, L., Nishimura, M., Yang, D. S., Mount, H. T. J., Westaway, D., & St George-Hyslop, P. H. (2001). Presenilin function: Connections to Alzheimer's disease and signal transduction. Biochemical Society Symposium, 67, 89-100. https://doi.org/10.1042/bss0670089