Role of the Presenilin1mediated Cleavage of Ecadherin

Phillippe Marambaud, PhD
Mount Sinai School of Medicine (New York, NY)
Year Awarded:
2002
Grant Duration:
April 1, 2002 to March 31, 2004
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2002061
Award Type:
Standard
Award Region:
US Northeastern

Role of the Presenilin1mediated Cleavage of Ecadherin

Details


Mutations in presenilin-1 (PS1) are responsible for familial Alzheimer's disease (FAD), also known as early-onset Alzheimer's disease. PS1 is found at the plasma membrane and is involved in cell-cell contacts. It interacts with E-cadherin, a cell surface molecule that facilitates cell-cell adhesions and has a crucial role in the structure of the synapse, the region involved in neuron communication. E-cadherin forms complexes with cytosolic proteins, like catenins, to link the actin cytoskeleton. The remodeling of cell-cell interactions is a central determinant for many functions, including tissue repair, cell migration and cell death. The molecular mechanisms involved in the disassembly of cell-cell associations are not clearly understood. It has been shown E-cadherin processing is mediated by PS1/gamma secretase activity. Dr. Marambaude is investigating whether PS1-mediated cleavage of E-cadherin disconnects the cadherin with the cytoskeleton and plays a role in the disassembly of cell-cell adhesions. He also plans to study the signaling pathways that are activated by the PS1/gamma secretase-mediated processing of E-cadherin and the subsequent disassembly of cadherin/catenin complexes. Finally, he will examine whether mutated PS1 in FAD abnormally affects its activity to cleave E-cadherin and thereby participating in the neuronal loss observed in Alzheimer's disease. This project will help to determine the usefulness of treatments using gamma-secretase inhibitors in altering the E-cadherin-dependent adhesion and signaling systems.

Publications

Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003 Sep 5;114(5):635-45. PubMed  

. Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, Baki L, Wen P, Efthimiopoulos S, Shao Z, Wisniewski T, Robakis NK. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002 Apr 15;21(8):1948-56. PubMed  

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