Presenilin function: connections to Alzheimer's disease and signal transduction.
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 beta-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 beta-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 beta-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.
Fraser
P E
PE
Department of Medicine, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
Yu
G
G
Lévesque
L
L
Nishimura
M
M
Yang
D S
DS
Mount
H T
HT
Westaway
D
D
St George-Hyslop
P H
PH
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D000818:Animals; D003598:Cytoskeletal Proteins / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008959:Models, Neurological; D015394:Molecular Structure; D020125:Mutation, Missense; D053764:Presenilin-1; D053766:Presenilin-2; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D015534:Trans-Activators; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D046911:Macromolecular Substances; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D015534:Trans-Activators; D051176:beta Catenin