|
|
 |
BIOGRAPHY:
Dr. St George-Hyslop is Assistant Professor, Department of Medicine, Division of Neurology, and Director, Center for Research in Neurodegenerative Disease, University of Toronto. He received a D.Sc. from the Faculty of Medicine, University of Ottawa, and an M.D. in internal medicine and in neurology from the Royal College of Physicians of Canada. He conducted postdoctoral research at the University of Toronto and at Harvard Medical School. Dr. St George-Hyslop was appointed as Instructor in Neurology at the Harvard Department of Neurology and Genetics and then assumed his current position in the University of Toronto Department of Medicine and later at the Center for Research in Neurodegenerative Disease. His honors include the Francis A. McNaughton Prize from the Canadian Neurologic Society and an Award for Medical Research from the Metropolitan Life Foundation. He was selected as a Medical Research Council of Canada Scholar in 1991, and he received the Gold Medal in Medicine from the Royal College of Physicians of Canada in 1994 and shared the 2001 Neuroscience Research Excellence Award from the Japan Neuroscience Society. In 1995 he became a member of the American Society for Clinical Investigation and he is a fellow of the Royal Society of Canada.
RESEARCH ABSTRACT SUMMARY:
Molecular Dissection of the Multiprotein, High Molecular Weight,
Membrane-Bound Presenilin Complexes
The presenilin proteins (PS1 and PS2) are homologous, polytopic,
transmembrane proteins that are necessary for the endoproteolytic
cleavage of several Type 1 transmembrane proteins, including the
amyloid precursor protein (APP). The cleavage of APP generates A-beta
and a series of C-terminal stubs (epsilon-stubs). Although PS1 and PS2
form independent, high molecular weight complexes, these complexes do
contain several common components. The other components of the PS1 and
PS2 complexes include nicastrin (a Type 1 transmembrane glycoprotein),
APH-1 (a polytopic transmembrane protein with no significant homology
to other proteins), and PEN-2 (a unique peptide with two transmembrane
domains). Glycosylation and trafficking of nicastrin to the cell
surface is necessary for the biological activity of the presenilin
complexes, and nicastrin preferentially binds to the mature presenilin
components (e.g., PS1 N- and C-terminal fragments). Conversely, the
absence of PS1 or PS2 destabilizes nicastrin. APH-1 appears to be a
stable component predominantly located in the ER and may represent the
initial scaffolding molecule. APH-1 binds to both mature and immature
species of nicastrin and presenilin. The role of PEN-2, which interacts
with other complex components through a conserved motif at the
C-terminus, is less clear. PEN-2 may be involved in final complex
activation or in modulating the relative balance of cleavage at the
A-beta40 and A-beta42 sites. Analysis of the presenilin complex
components may provide clues to a novel form of endoproteolytic
cleavage (regulated intramembranous proteolysis) and to potential
therapeutics for Alzheimer disease.
Photo: Birgit C. An der Lan
|
