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Peter St George-Hyslop’s research has been primarily directed toward elucidating the mechanisms causing human neurodegenerative disease, with research into the molecular basis for Alzheimer Disease constituting the main focus of this work. His laboratory discovered that Alzheimer’s disease is etiologically heterogeneous, an observation that subsequently had a profound effect on the design of both clinical and basic research paradigms on this disease. His laboratory directly led to the discovery of multiple genes associated with AD, including presenilin 1, presenilin 2, nicastrin, and SORL1. He co-led in the discovery of two other genes, the amyloid precursor protein with J. Gusella, and apolipoprotein E with A. Roses. More recently, as a member of the Alzheimer’s Disease Genetics Consortium, he used Genome Wide Association Study (GWAS) methods in the largest study of AD genetics to that time, to identify at least 9 novel AD genes associated with late onset AD.
Dr. St George-Hyslop’s laboratory has shown that: aberrant APP processing and accumulation of the Ab peptide fragment is central to the pathogenesis of AD; that cerebral Aβ deposition is the earliest pathological feature in pre-symptomatic cases of familial AD; and that overproduction of Aβ is a consequence of AD-causing clinical mutations in several AD genes including PS1 (in collaboration with D. Selkoe and M Citron) and SORL1. Using genetic methods, his laboratory has shown that several of the known AD genes have additive effects and are thus likely to function within the same metabolic or signaling pathway. One of these pathways relates to APP processing and Aβ peptide accumulation and aggregation into a neurotoxic oligomers. However, St George Hyslop's work also implicates, amongst others, pathways involved in innate immune and inflammatory responses to protein aggregates. Using biochemical, cellular, and molecular biological methods, his laboratory has begun to decipher the molecular mechanisms by which genetic variants in these genes and pathways cause AD.
One particular area of his research that arose from his work on AD and the presenilin proteins has turned out to have major implications for a previously unrecognized basic biological process - Regulated Intramembranous Proteolysis". Thus, he has shown that the presenilins, nicastrin, PEN-2 and APH-1 proteins are components of a tetrameric protein complex (presenilin complex /γ-secretase complex). This complex is the catalytic unit that performs the intramembranous γ- and ε-secretase cleavages of the transmembrane domains of APP and Notch to generate Aβ and Notch Intracellular Domain respectively. This process has been termed "Regulated Intramembranous Proteolysis". He has identified a new regulatory component of the presenilin complexes - TMP21. TMP21 differentially regulates γ- and ε-site secretase cleavage activities. To work out structural mechanics of this unusual enzyme complex, St George-Hyslop has used single particle electron microscopy to generate a 15Å resolution 3D model of the PS1 complex in the presence or absence of small molecule inhibitors. Cumulatively, St George-Hyslop’s scientific contributions in this area have provided otherwise unattainable insights into a novel form of protein processing that is essential both for several critical physiological signal transduction events (Notch signaling), and for a key event mechanism underlying AD (Aβ generation). Selective modulation of the presenilin-mediated production of Aβ while sparing Notch signaling remains a candidate therapeutic approach in the treatment of AD.
Work in Dr. St George-Hyslop’s group has led to the generation of several superb transgenic mouse models for Alzheimer Disease and Frontotemporal Lobar Degenerations. He has used the Alzheimer transgenic mice (TgCRND8) to show that immunization with Aβ reduces both neuropathological and cognitive deficits in these mice. This result has suggested that Aβ immunization, as well as other therapies directed at Aβ biology, may have utility as mechanism-based, disease-modifying treatments and/or preventions of Alzheimer’s Disease in humans. This idea has recently received support from some human trials, which have suggested partial benefit to patients with early/mild AD. Moreover, he has defined both the immune epitope in Aβ that is targeted by therapeutically effective Aβ-vaccination. This information will serve as a basis both for improved antigens and for the generation of novel compounds to mimic the effects of antigen:antibody binding. Indeed, he and his team have found a promising series of compounds epitomized by scyllo-inositol that inhibit Aβ oligomer assembly and toxicity in preclinical animal models of AD. This compound has recently completed Phase 2 clinical trials in humans.
In addition to his work on AD, St George-Hyslop has made major contributions to the molecular genetics and molecular neurobiology of Frontotemporal C. elegans models of FUS- and TDP-43-dependent forms of FTLD/MND. He has used these models to show that FUS and TDP-43 mutations cause FTLD/MND by inducing these proteins to aggregate into a novel type of neurotoxic protein aggregate – namely hydrogel-derived aggregates. These aggregates differ from traditional amyloid aggregates in several important biophysical parameters. He has shown that the effects of SOD1 mutations in Familial ALS/MND likely arise from a gain-of-toxic function effect that is independent of SOD1 catalytic activity, and that the copper chaperone for SOD1 (CCS) gene is not the site of mutations causing ALS in families lacking SOD1 mutations.
St George-Hyslop has made contributions to the genetics of other neurodegenerative diseases including Spinocerebellar Ataxias, Dystonia/Parkinsonism, cortico-basal Ganglionic degeneration, Benign Hereditary Chorea and most recently Progressive Supranuclear Palsy, where he has used GWAS methods to identify tau and several new genes involved in vesicular trafficking and innate immunity as risk factors for PSP.
St George-Hyslop has also provided critical discoveries on the molecular genetics of several non-neurological diseases such as hereditary Palmar Plantar Hyperkeratosis (which is sometimes associated with breast and esophageal cancer), hereditary cataracts, polycystic kidney disease, and Inflammatory Bowel Disease (IBD), where he has shown that one form of IBD arises from mutations in the OCTN1 and OCTN2 genes.
Peter St George-Hyslop is the acclaimed director of the Tanz Centre for Research in Neurodegenerative Disease and a professor in the University of Toronto’s Division of Neurology. He received his M.D. from the University of Ottawa, specialized in internal medicine and neurology and conducted postdoctoral research at the University of Toronto and at Harvard Medical School.
Prof. St George-Hyslop was an instructor in neurology and genetics at Harvard University and assistant physician in the Departments of Neurology and Genetics at Massachusetts General Hospital before assuming his current position at the University of Toronto in 1991, where now he holds the rank of University Professor, the University’s highest academic post.
Dr. St George-Hyslop's honours include the Francis A. McNaughton Prize from the Canadian Neurological Society and the Award for Medical Research from the Metropolitan Life Foundation. He was a Medical Research Council of Canada (now the Canadian Institutes of Health Research) Scholar in 1991 and a Distinguished Scientist in 2000. He received the Gold Medal in Medicine from the Royal College of Physicians of Canada in 1994 and the Michael Smith Award from the Canadian Institutes of Health Research in 1997. In 1995, he became a member of the American Society for Clinical Investigation, and he is a fellow of the Royal Society of Canada. In 2004 he was awarded the Oon International Award in Preventive Medicine from the University of Cambridge, and in 2007 he was elected as a foreign member to the Institute of Medicine of the National Academy of Sciences. Dr. St George Hyslop is a Howard Hughes International Scholar, Fellow of the Royal Society of London. He was awarded the BIAL Merit Award in Medical Sciences in and was named a Fellow of the American Neurological Association also in 2013. He was awarded the Dan David Prize in 2014.