Presenilin 1 and cadherins: stabilization of cell-cell adhesion and proteolysis-dependent regulation of transcription.
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 gamma-secretase, which generates the carboxyl end of beta-amyloid peptide (gamma-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/gamma-secretase activity, promoting disassembly of adherens junctions, and resulting in the increase of cytosolic beta-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 (epsilon-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.
Parisiadou
Loukia
L
Division of Animal and Human Physiology, Department of Biology, University of Athens, Athens, Greece.
Fassa
Angeliki
A
Fotinopoulou
Angeliki
A
Bethani
Ioanna
I
Efthimiopoulos
Spiros
S
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D010450:Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology; D053764:Presenilin-1
D015820:Cadherins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human