- ASSOCIATE PROFESSOR Psychiatry
ResearchIn order to understand the cause of Alzheimer's disease we study the function of Presenilin-1 (PS1), a protein mutated in most cases of familial Alzheimer's disease (FAD). PS1/gamma-secretase activity controls the proteolytic cleavage of many type I transmembrane proteins like APP, Notch-1, ErbB4 and E- and N-cadherin. In our effort to understand the physiological function of PS1 in the cells and the effect that its mutations have on the normal function of the brain we identified new proteins that interact with it.
We found that PS1 interacts with ephrinB proteins, which are type I transmembrane proteins that function as ligands for the ephrinB receptors (EphBs). The ephrinB-EphB system is present at the neuronal synapse in the brain where it transmits signals from both the receptor and the ligand thus constituting a bi-directional signaling system. This system regulates very important cellular processes in development and adulthood including cell migration, axon guidance, angiogenesis and synaptic plasticity. It also participates in the regulation of two forms of long-term synaptic plasticity that are important for information storage in the brain, the long-term potentiation (LTP) and the long-term depression (LTD). PS1/gamma-secretase regulates the proteolytic processing of both ephrinB and EphB proteins and the EphB-induced phosphorylation of Src kinase, a process initiated by the eprhinB-EphB interaction. PS1 mutations in familial Alzheimer's disease may thus disrupt the normal function of the ephrinB-EphB system in the brain affecting important brain functions.
We also found that PS1 affects the expression of neuronal microRNAs (miRs). MiRs are short non-coding RNAs that regulate gene expression usually by binding to the 3΄-untranslated region of target messenger RNAs (mRNAs) promoting their degradation and/or inhibiting their translation. MiRs control a variety of physiological processes in the nervous system through these mechanisms such as neuronal survival, differentiation, synaptic plasticity and memory. Emerging evidence supports a role for miR dysregulation in psychiatric and neurodegenerative disorders. Mutations in PS1 found in Alzheimer’s disease may impair neuronal physiology by affecting miR expression.
Dr. Georgakopoulos research goal is to study the role that PS1 may have in synaptic structure and function and in vascular integrity by affecting the physiological processing of ephrinB proteins and their EphB receptors, the ephrinB-EphB-mediated signaling and the expression of miRs.
Robakis NK, Georgakopoulos A. Allelic Interference: A Mechanism for Trans -Dominant Transmission of Loss of Function in the Neurodegeneration of Familial Alzheimer's Disease. Neuro-degenerative diseases 2013 Sep;.
Barthet G, Dunys J, Shao Z, Xuan Z, Ren Y, Xu J, Arbez N, Mauger G, Bruban J, Georgakopoulos A, Shioi J, Robakis NK. Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiology of aging 2013 Feb; 34(2).
Barthet G, Georgakopoulos A, Robakis NK. Cellular mechanisms of γ-secretase substrate selection, processing and toxicity. Progress in neurobiology 2012 Aug; 98(2).
Georgakopoulos A, Xu J, Xu C, Mauger G, Barthet G, Robakis NK. Presenilin1/gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk binding protein. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2011 Oct; 25(10).
Litterst c, Georgakopoulos a, Shioi j, Ghersi e, Wisniewski t, Wang r, Ludwig a, Robakis nk. Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase processing pathways of EphB2 receptor. J. Biol. Chem 2007 June; 282(22).
georgakopoulos a, litterst c, ghersi e, baki l, xu c, serban g, robakis nk. Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 2006 Mar 22; 25(6).
marambaud p, shioi j, serban g, sarner s, georgakopoulos a, nagy v, baki l, wen p, efthimiopoulos s, shao z, wisniewski t, robakis nk. A presenilin-1/g-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 2002; 21(8).
baki l, marambaud p, efthimiopoulos s, georgakopoulos a, wen p, cui w, shioi, j, koo e, ozawa m, friedrich jr v, robakis nk. Presenilin1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. Proc Natl Acad Sci U S A 2001 Feb 27; 98(5).
georgakopoulos a, marambaud p, robakis nk, baki l. Presenilin-1 is a regulatory component of the cadherin cell adhesion complex: Implications for Alzheimer's Disease. In: iqbal k, sisodia s, winblad b, editors. Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics. Chichester, England, John Willey and Sons; 2001.
georgakopoulos a, marambaud p, friedrich jr, shioi j, efthimiopoulos s, robakis nk. Presenilin-1: A Component of Synaptic and Endothelial Adherens Junctions. In: growdon jh, wurtman rj, corkin s, nitsch rm, editors. The Molecular Basis of Dementia. New York, New York Academy of Sciences; 2000.
georgakopoulos a, marambaud p, efthimiopoulos s, shioi j, cui w, li hc, schutte m, gordon r, holstein gr, martinelli g, mehta p, friederich vl jr, robakis nk. Presenilin-1 forms complexes with the cadherin/catenin cell-cell adhesion system and is recruited to intercellular and synaptic contacts. Mol Cell 1999 Dec; 4(6).
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Dr. Georgakopoulos did not report having any of the following types of financial relationships with industry during 2014 and/or 2015: consulting, scientific advisory board, industry-sponsored lectures, service on Board of Directors, participation on industry-sponsored committees, equity ownership valued at greater than 5% of a publicly traded company or any value in a privately held company. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
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