[HTML][HTML] A CBP binding transcriptional repressor produced by the PS1/ϵ-cleavage of N-cadherin is inhibited by PS1 FAD mutations

P Marambaud, PH Wen, A Dutt, J Shioi, A Takashima… - Cell, 2003 - cell.com
P Marambaud, PH Wen, A Dutt, J Shioi, A Takashima, R Siman, NK Robakis
Cell, 2003cell.com
Abstract Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms
complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic
functions. Here, we show that a PS1-dependent γ-secretase protease activity promotes an ϵ-
like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA
receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates
the ϵ-cleavage of N-cadherin. N-Cad/CTF2 binds the transcription factor CBP and promotes …
Abstract
Presenilin1 (PS1), a protein implicated in Alzheimer's disease (AD), forms complexes with N-cadherin, a transmembrane protein with important neuronal and synaptic functions. Here, we show that a PS1-dependent γ-secretase protease activity promotes an ϵ-like cleavage of N-cadherin to produce its intracellular domain peptide, N-Cad/CTF2. NMDA receptor agonists stimulate N-Cad/CTF2 production suggesting that this receptor regulates the ϵ-cleavage of N-cadherin. N-Cad/CTF2 binds the transcription factor CBP and promotes its proteasomal degradation, inhibiting CRE-dependent transactivation. Thus, the PS1-dependent ϵ-cleavage product N-Cad/CTF2 functions as a potent repressor of CBP/CREB-mediated transcription. Importantly, PS1 mutations associated with familial AD (FAD) and a γ-secretase dominant-negative mutation inhibit N-Cad/CTF2 production and upregulate CREB-mediated transcription indicating that FAD mutations cause a gain of transcriptional function by inhibiting production of transcriptional repressor N-Cad/CTF2. These data raise the possibility that FAD mutation-induced transcriptional abnormalities maybe causally related to the dementia associated with FAD.
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