PS1Nicastrin Interaction and Role in Trafficking

Gopal Thinakaran, PhD
University of Chicago (Chicago, IL)
Year Awarded:
2001
Grant Duration:
April 1, 2001 to March 31, 2003
Disease:
Alzheimer's Disease
Award Amount:
$199,930
Grant Reference ID:
A2001074
Award Type:
Standard
Award Region:
US Midwestern

PS1Nicastrin Interaction and Role in Trafficking

Details


It is well known that presenilin proteins (PS-1 and PS-2) and other proteins interact to generate amyloid beta protein. Recently, researchers at the University of Toronto (with whom Dr. Thinakaran is collaborating) identified one of the proteins, Nicastrin, that interacts with presenilins. A better understanding of the association between presenilins and Nicastrin will shed more light on the mechanisms involved in amyloid beta production, and perhaps lead to new therapies for AD aimed at reducing amyloid beta deposits in the brain. Some studies also indicate that presenilins may be involved in assisting APP (the precursor for amyloid beta) in reaching appropriate destinations within the cell. Dr. Thinakaran is examining whether presenilins direct other proteins to their destinations. He will explore this issue by studying two proteins that resemble APP and others that have structures different from that of APP. It is hoped that these latter studies will help scientists understand what presenilins normally do. The information gained from studies like this will be critical to determining whether presenilins can be considered as appropriate targets for the treatment of AD.

Publications

Leem, J.Y., Vijayan, S., Han, P., Cai, D., Machura, M., Lopes, K.O., Veselits, M.L., Xu, H., and Thinakaran, G. (2002) Presenilin 1 is required for maturation and surface accumulation of nicastrin. J. Biol. Chem. 277:19236-19240,  

Leem, J.Y., Saura, C.A., Pietrzik, C., Christianson, J., Wanamaker, C., King, L.T., Veselits, M.L., Tomita, T., Gasparini, L., Iwatsubo, T., Xu, H., Green, W., Koo, E.H., and Thinakaran, G. (2002) A role for presenilin 1 in regulating the delivery of amyloid precursor protein to the cell surface. Neurobiol. Dis. 11:64-82.  

Cai, D., Leem, J.Y., Greenfield, J.P., Wang, P., Wang, R., Lopes, K.O., Kim, S.H., Zhen, H., Greengard, P., Sisodia, S.S., Thinakaran, G., and Xu, H. (2002) Presenilin-1 regulates intracellular trafficking and cell surface delivery of Beta APP. J.Biol. Chem. 278:3446-3454.  

Luo, W., Wang, H., Li, H., Kim, B.S., Shah, S., Lee, H.J., Thinakarant, G., Kim, T.W., Yu, G., and Xu, H. (2003) PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J. Biol. Chem. 278:7850-7854.  

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