Paul E. Fraser
ProfessorPhD, University of Toronto
Toronto Western Hospital, Krembil Discovery Tower
6th Floor, 6KD-402
60 Leonard Avenue, M5T 2S8
Toronto, Ontario, Canada
Email Dr. Paul Fraser
Role of Amyloid & Presenilin Proteins in Alzheimer’s Disease
Research in our laboratory focuses on the biochemistry and biophysics of amyloid plaques and their relationship to sporadic and familial forms of Alzheimer’s disease. Plaques are a principal pathological feature of Alzheimer’s disease and appear as abnormal accumulations of fibrous or thread-like structures within the brain. These plaques are assembled by the misfolding and aggregation of the amyloid-beta (Abeta) protein. We have been studying its properties with an emphasis on the factors responsible for the transition from the normal to diseased fibrous state, the ability of aggregated Abeta‚ to kill nerve cells in culture, and the mechanism by which this is accomplished. Considerable advances have been made in this area and we are expanding our efforts to look for modulators of plaque formation as well as the cellular receptors which we feel are responsible for amyloid’s “killer” action. Our ultimate goal is to understand the events that culminate in these abnormal and detrimental proteins and the development of drugs capable of controlling these processes. These investigations are relevant to both the sporadic and familial forms of Alzheimer’s disease which exhibit identical amyloid pathology but differ only in their rate of progression.
In conjunction with our amyloid research and drug development, our group has been concentrating its efforts on understanding the biochemistry and structural biology of the presenilin family of proteins. Mutations in the presenilin genes are the major cause of inherited forms of Alzheimer’s disease and we have been examining the location and expression of these proteins in neuronal cells and their relationship to the pathology of Alzheimer’s disease. This biochemical and molecular biological work is complemented by our examination of the three-dimensional organization of particular regions of the presenilin protein using a variety of biophysical techniques. Through these two approaches, we will be able to provide details on presenilin function and the molecular mechanism by which this is achieved. The importance of these studies is that they enable us to understand the earliest events in Alzheimer’s disease and allow us to develop novel approaches to the treatment of a principal cause of Alzheimer’s disease.
List of Key Publications:Link to Pubmed Publications
Chen, F., Hasegawa, H., Schmitt-Ulms, G., Kawarai, T., Bohm, C., Katayama, T., Gu, Y. Sanjo, N., Glista, M., Rogaeva, E., Wakutani, Y., Piquard, R.P., Ruan, X., Tandon, A., Checler, F., Marambaud, P., Hansen, K., Westaway, D., St George-Hyslop P. and Fraser, P.E. (2006) TMP21 is a presenilin complex component that modulates - but not e-secretase activity. Nature 440: 1208-12.
Dorval, V. and Fraser, P.E. (2006) SUMO modification of natively unfolded proteins tau and alpha-synuclein. J. Biol. Chem. 281: 9919-24.
Gu, Y., Sanjo, N., Chen, F., Hasegawa, H., Petit, A., Ruan, X., Li, W., Shier, C., Kawarai, T., Schmitt-Ulms, G., Westaway, D., St George-Hyslop, P. and Fraser, P.E. (2004) The presenilin proteins are components of multiple membrane-bound complexes which have different biological activities. J. Biol. Chem. 279: 31329-36.
Yang, D-S., Tandon, A., Chen, F., Yu, G., Arawaka, S., Yu, H., Hasegawa, H., Duthie, M. Ramabhadran, T.V., Mathews, P.M., Gandy, S.E., Mount H.T.J., St George-Hyslop, P. and Fraser,P.E. (2002) Mature glycosylation and secretory trafficking of nicastrin modulate its binding to presenilins. J. Biol. Chem. 277:28135-42.