FUNCTION OF ALZHEIMER DISEASE PRESENILIN 2

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Alzheimer's Disease (AD) is a devastating neurodegenerative disorder that results in loss of memory, cognition, and aberrant behavior. The incidence of AD in the USA is estimated to be approximately 4 million today, but is expected to rise to 14 million by the year 2020 due to an anticipated increase in life expectancy. The mechanisms that cause AD are not known and there is no known cure. Mutations in three genes have been shown to be associated with development of AD; the beta amyloid precursor protein, and two highly related genes, presenilin 1 and presenilin 2 (PS2). Neither the functions of these three genes in neurons nor the mechanisms by which mutations in these genes cause AD are known. Interestingly most AD-associated mutations occur in the genes for the presenilins which are ubiquitously expressed. Evidence indicates presenilins function in development and may also be involved in the regulation of programmed cell death (apoptosis). We and others have shown that overexpression of PS2 in both dividing and non dividing cells induces apoptosis. Furthermore, we have found that overexpression of PS2 in dividing cells leads to the arrest of cells in the G1 phase of the cell cycle. Interestingly, this cell cycle arrest is potentiated by the FAD PS2(N141I) mutation. We propose to study in detail the mechanisms by which PS2 overexpression leads to cell cycle arrest and the relationship to apoptosis and AD. In a companion effort we used the yeast 2-hybrid system to identify proteins that interact with PS2. A number of putative interactors were found to bind the hydrophilic loop and C- terminal sequences of PS2. These include a novel calcium-binding myristoylated protein (which we have termed CALMYRIN) which binds PS2 loop sequences, and a novel protein which contains ubiquitin- like and ubiquitin-association motifs which binds to both the C- terminal and loop sequences of presenilins. Interestingly, calmyrin does not bind as avidly to the corresponding loop sequences of PS1 and to our knowledge is the first protein that has been found to preferentially bind one presenilin and not the other. Calmyrin causes cell death when overexpressed, and acts synergistically with PS2 so that dual overexpression results in twice the level of death compared to expression of each protein individually. In order to build a more global understanding of presenilins and the proteins with which they interact we propose to study and characterize these putative interactors. Eventually we hope these studies will contribute to a better understanding of how presenilins function in normal cells and in AD.