Presenilin 1 and cadherins: Stabilization of cell-cell adhesion and proteolysis-dependent regulation of transcription

Loukia Parisiadou, Angeliki Fassa, Angeliki Fotinopoulou, Ioanna Bethani, Spiros Efthimiopoulos*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

25 Scopus citations

Abstract

Presenilin-1 (PS1) has gained intensive attention in relation to Alzheimer's disease, since it has been shown that PS1 mutations are linked to familial Alzheimer's disease (FAD), and that PS1 is a member of the high molecular weight complex of γ-secretase, which generates the carboxyl end of β-amyloid peptide (γ-cleavage). A parallel line of evidence suggests that upon formation of cell-cell contacts, presenilin colocalizes with cadherins at the cell surface and stabilizes the cadherin-based adhesion complex. Under conditions stimulating cell-cell dissociation, cadherins are processed by a PS1/γ-secretase activity, promoting disassembly of adherens junctions, and resulting in the increase of cytosolic β-catenin, which is an important regulator of the Wnt/Wingless signaling pathway. PS1 also controls the cleavage of a number of transmembrane proteins at the interface of their transmembrane and cytosolic domains (ε-cleavage), producing intracellular fragments with a putative transcriptional role. Remarkably, cleavage of N-cadherin by PS1 produces an intracellular fragment that downregulates CREB-mediated transcription, indicating a role of PS1 in gene expression. PS1 mutations associated with FAD abolish production of the N-cadherin intracellular fragment and thus fail to suppress CREB-dependent transcription. These findings suggest an alternative explanation for FAD that is separate from the widely accepted 'amyloid hypothesis': dysfunction in transcription regulatory mechanisms.

Original languageEnglish (US)
Pages (from-to)184-191
Number of pages8
JournalNeurodegenerative Diseases
Volume1
Issue number4-5
DOIs
StatePublished - 2004

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Cadherin
  • Presenilin

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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