Peter Henry St George-Hyslop, OC, FRS, FRSC, FRCPC

Overview

Currently not actively seeing patients. My areas of expertise are in neurodegenerative diseases (especially disorders of memory, cognition and dementia) and in inherited disorders of the nervous system.

Academic Appointments

  • Professor of Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Gender

  • Male

Credentials & Experience

Honors & Awards

  • 2021 Margolese National Brain Disorders Prize (Canada)
  • 2018 Officer, Order of Canada (Canada)
  • 2017 Ryman Prize (New Zealand)
  • 2014 Dan David Prize, Tel Aviv (Israel)
  • 2012 BIAL Merit Award for Medical Research (Portugal)
  • 2009 Fellow of the Academy of Medical Sciences (UK)
  • 2007 Foreign Member, US National Academy of Medicine
  • 2007 Howard Hughes Medical Institute International Scholar Award
  • 2005 Matthew T. Moore Distinguished Lecturer, American Association of
  • Neuropathology
  • 2004 Fellow, Royal Society of London
  • 2002 Howard Hughes Medical Institute International Scholar Award
  • 2000 The F.E. Bennett Award, American Neurological Association
  • 1997 Howard Hughes Medical Institute International Scholar Award
  • 1996 The Potamkin Prize, American Academy of Neurology
  • 1993 The Gold Medal in Medicine, Royal College of Physicians of Canada

Research

St George-Hyslop pioneered the use of molecular genetics to Alzheimer Disease (AD)1,2. In 1985, St George-Hyslop was the first to apply molecular genetic Restriction Fragment Length Polymorphism (RFLP) markers and genetic linkage strategies to map genes for early onset familial Alzheimer’s disease (EOAD). In 2003, he led the collection of data and biosamples for a Canadian case-control cohort (GenADA cohort) for sporadic Late Onset AD (LOAD) well before the current GWAS era was in vogue. This cohort has, and continues to contribute to breakthroughs by international genetics consortia to which St George-Hyslop belongs (i.e. Alzheimer’s Disease Genetics Consortium – ADGC; and International Genetics of Alzheimer Project - IGAP). St George-Hyslop was director of the Tanz Centre for research in neurodegenerative diseases that the University of Toronto, the Founding Director of the

University of Cambridge Biomedical Research Unit in Dementia, and led several Wellcome Trust funded collaborations on AD and Amyotrophic lateral sclerosis / Fronto-Temporal Lobar Degeneration (ALS/FTLD) involving Cambridge and Toronto.

St George-Hyslop’s research program has led to: 1. The collection and curation of crucial clinical research cohorts comprised of families with monogenic forms of AD, and of collections of sporadic cases and normal controls. 2. Identified multiple genes causing early onset Alzheimer’s disease (EOAD)1-5; late-onset AD (LOAD)6-14; and related disorders such as PSP15,16; 3. Defined the functional pathways in which these genes work, and defined the three-dimensional structure of some of their encoded proteins7-23; 4. Identified novel molecular therapeutic targets24; 5. Recognised disease stages that might be most amenable to treatment25; and 6. Insights into other genetic disorders.

  1. Collection and curation of crucial clinical research datasets: 1985, in collaboration with Ron Polinsky, Dan Pollen, David Drachman, Jean François Foncin and Amalia Bruni, St George-Hyslop collected multiple families affected by autosomal dominant familial AD. These extended multigenerational pedigrees were crucial in his subsequent discovery of the PS1, PS2 and TREM2 genes. These families have also been recruited into subsequent translational and clinical studies such as the DIAN prospective study of autosomal dominant AD. In 1990, he began collection of sporadic cases and controls, which contributed to the discovery of the association of apolipoprotein E gene with late-onset AD by Allen Roses and himself. In 2003, well before the current GWAS era, he led the collection of data and biosamples for one of the first case-control cohort studies of late onset AD (the Canadian GenADA cohort). This cohort has, and continues to contribute to breakthroughs by international genetics consortia to which St George-Hyslop belongs (i.e. Alzheimer’s Disease Genetics Consortium – ADGC; and International Genetics of Alzheimer Project - IGAP). Crucially these well-curated datasets led to the discovery of multiple disease-causing mutations (e.g. in TREM2, PLCG2, ABI3 and SORL1).

  2. Identifying genes causing AD and related disorders: St George-Hyslop pioneered the use of molecular genetics to AD2. Together with his collaborators collaborators, St George-Hyslop cloned and/or mapped, and then identified disease-associated sequence variants in three genes associated with early onset AD (EOAD)3-5; ≥20 genes associated with late-onset AD (LOAD)6-14; and multiple genes associated with PSP15,16.

  3. Defining the functional pathways in which neurodegenerative disease genes work: He characterised the molecular function, and in some cases, the three-dimensional structure of proteins (to 2.3Å-17Å resolution) encoded by AD, ALS/FTLD and PSP risk genes7-23. These studies helped change our understanding of the pathogenesis of these diseases (e.g. changing the field’s view on the role of microglia in AD, showing microglia to be central players8-14). Crucially, this work also identified several previously unrecognised fundamental neurobiological processes (e.g. presenilin-dependent regulated intramembranous proteolysis of membrane proteins17-20; the role of intrinsically disordered proteins in forming reversible condensates involved in the transport and function of ribonucleoprotein granules in supporting local new protein synthesis in synaptic axon terminals21-23).

  4. Identifying molecular therapeutic targets: St George-Hyslop’s work in AD supported the notion that Aβ is a rational therapeutic target for AD, revealing anti-Aβ immunotherapies as a potential therapeutic strategy24 - a result tentatively supported by recent re-analysis human trial data for aducanumab, an anti-Aβ immunotherapy. His work on FTLD/ALS has highlighted several new or therapeutic targets (e.g. proteins serving as chaperones and post-translational modifying enzymes21-23).

  5. Identifying disease stages that might be most amenable to treatment: St George-Hyslop’s prescient neuropathology studies in 1998 with Lippa, in genetically at-risk carriers of PS1 mutations, revealed that cerebral Aβ accumulation antedates symptom-onset by many years25. This result, was replicated more than a decade layer by the DIAN study, and underpins the current focus on conducting clinical trials in early stage AD.
  6. Insight into other genetic diseases: 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.

St George-Hyslop’s work (448 peer reviewed papers) has been cited more than 71,549 times. 54 of his primary research papers (i.e. not reviews) have been cited >250 times; 12 papers being cited >1000 times; two papers >2250 times; and two papers >4250 times. H-index = 121, i10 index = 404 (Google Scholar, update: 12/02/2021)

SELECTED CITATIONS: (From >444 peer-reviewed papers)

1Science 235,885,1987; 2Nature 347,194,1990; 3Science 235, 880,1987; 4Nature 375, 754, 1995; 5Nature 376,775,1995; 6Neurology 43,1467,1993; 7Nat Genet 39,168,2007; 8N Engl J Med 368,117,2013; 9Nat Genet 43,436,2011; 10Nat Genet 45,1452,2013; 11Nat Genet 49,1373,2017; 12Nat Genet 51,414,2019; 13Nat Med 25,152,2019; 14Science 360,2018; 15Nat Genet 43,699;2011; 16Neuron 87,963,2015; 17Nature 407,48,2000; 18Nat Cell Biol 3,751,2001; 19Structure 22,125,2014; 20Nat Med 3,67,1997; 21Neuron 88,678,2015; 22Cell 173,720,2018; 23Cell 179,147,2019; 24Nature 408,979,2000; 25Lancet 352,1117,1998).

Selected Publications

  1. Understanding physiological and pathological phase transitions of intrinsically disordered proteins
    1. Murakami T, Qamar S, Lin JQ, Kaminski Schierle GS, Rees E, Miyashita A, Costa AR, Dodd RB, Chan FTS, Michel CH, Kronenberg-Versteeg D, Li Y, Yang SP, Wakutani Y, Meadows W, Ferry RR, Dong L, Tartaglia GG, Giorgio Favrin7, Lin WL, Dickson DW, Zhen M, Ron D, Schmitt-Ulms G, Fraser PE, Shneider NA, Holt C, Vendruscolo M, Kaminski CF, St George-Hyslop PH. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron. 2015 Nov; 88(4):678-90. PMC4660210
    2. Qamar S, Wang G, Randle SJ, Ruggeri FS, Varela JA, Lin JQ, Phillips EC, Miyashita A, Williams D, Ströhl F, Meadows W, Ferry R, Dardov VJ, Tartaglia GG, Farrer LA, Kaminski Schierle GS, Kaminski CF, Holt CE, Fraser PE, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. FUS Phase is Modulated by a Molecular Chaperone and by Methylation of Arginine Cation-π Interactions. Cell. 2018, 173, 720–734. PMC5927716
    3. 3. Liao, YC., Fernandopulle, M., Wang G., Choi, H., Hao, L. Drerup, C.M., Qamar, S., Nixon-Abell, J., Shen, Y., Meadows, W., Vendruscolo, M., Knowles, T.P.J., Nelson, M., Czekalska, M., Musteikyte, G., Patel, R., Stephens, C., Pasolli, A., Forrest, L., St George-Hyslop, P., Lippincott-Schwartz, J., Ward, M.E.RNA granules hitchhike on lysosomes for long-distance transport, using annexin A11as a molecular tether. Cell, 2019 Sep 19;179(1):147-164 (2019). PMC6890474
  2. Development of novel tools for assessment of physiological and pathological phase transitions of intrinsically disordered proteins forming biomolecular condensates
    1. Shen Y, Ruggeri FS, Vigolo D, Kamada A, Qamar S, Levin A, Iserman C, Alberti S, St George-Hyslop PS, Knowles TPJ. Biomolecular condensates undergo a generic shear-mediated liquid-to-solid transition. Nature Nanotechnol. 2020 15(10):841-847: doi: 10.1038/s41565-020-0731-4. doi: 10.1038/s41565-020-0731-4. PMID: 32661370; PMCID: PMC7116851.
    2. Krainer G, Welsh TJ, Joseph JA, Espinosa JR, Wittmann S, de Csilléry E, Sridhar A, Toprakcioglu Z, Gudiškyt? G, Czekalska MA, Arter WE, Guillén-Boixet J, Franzmann TM, Qamar S, St George-Hyslop P, Hyman AA, Collepardo-Guevara R, Alberti S, Knowles TPJ. Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions. Nat Commun. 2021 12(1):1085. PMID: 33597515; PMCID: PMC7889641.
    3. Arter WE, Qi R, Krainer G, Welsh TJ, Xu Y, St George-Hyslop PH, Alberti S, Knowles TPJ. Rapid Generation of Protein Condensate Phase Diagrams Using Combinatorial Droplet Microfluidics bioRxiv 2020.06.04.132308; /doi.org/10.1101/2020.06.04.132308
    4. Shen Y, Ruggeri FS, Vigolo D, Kamada A, Qamar S, Levin A, Iserman C, Alberti S, St George-Hyslop PS, Knowles TPJ. Biomolecular condensates undergo a generic shear-mediated liquid-to-solid transition. Nature Nanotechnol. 2020 15(10):841-847: doi: 10.1038/s41565-020-0731-4. PMC7116851
  3. Genetic association and functional genetics of AD genes involved in endocytosis and endosome biology SORL1, ABCA7
    1. Rogaeva E, Meng Y, Lee JH, Gu YJ, Kawarai K, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, lnzelberg R, Hampe W, Bujo H, Song Y, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux RP, Farrer LA, St George-Hyslop The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer's Disease. Nature Genetics. 2007, 39:168-177. PMC2657343
    2. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015; 77(2):215-27. PMC4367199
    3. Satoh K, Abe-Dohmae S, Yokoyama S, St George-Hyslop P, Fraser PE. ABCA7 Loss of Function Alters Alzheimer Amyloid Processing. J Biol Chem. 2015, 290(40):24152-24165. PMC4591804
    4. Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, NortonJ, Budde J, Bertelsen S, Jeng AT, Cooper B, Skorupa T, Carrell D, Levitch D, Hsu S, Choi J, Ryten M; UK Brain Expression Consortium, Hardy J, Ryten M, Trabzuni D,Weale ME, Ramasamy A, Smith C, Sassi C, Bras J, Gibbs JR, Hernandez DG, LuptonMK, Powell J, Forabosco P, Ridge PG, Corcoran CD, Tschanz JT, Norton MC, MungerRG, Schmutz C, Leary M, Demirci FY, Bamne MN, Wang X, Lopez OL, Ganguli M, Medway C, Turton J, Lord J, Braae A, Barber I, Brown K; Alzheimer’s Research UKConsortium, Passmore P, Craig D, Johnston J, McGuinness B, Todd S, Heun R, KölschH, Kehoe PG, Hooper NM, Vardy ER, Mann DM, Pickering-Brown S, Brown K, Kalsheker N, Lowe J, Morgan K, David Smith A, Wilcock G, Warden D, Holmes C, Pastor P, Lorenzo-Betancor O, Brkanac Z, Scott E, Topol E, Morgan K, Rogaeva E, Singleton AB, Hardy J, Kamboh MI, St George-Hyslop P, Cairns N, Morris JC, Kau, JS, Goate AM. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease. Nature. 505(7484):550-4. doi:10.1038/nature12825 PMID: 24336208 (2014). PMC4050701
  4. Genetic and functional studies on TREM2, CD33, PLCG2 and ABI3 microglial genes
    1. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J; Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013; 368(2):117-27. PMC3631573
    2. Sims R, van der Lee SJ, Naj A, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle J, Boland A, Raybould R.. St George-Hyslop P.. GERAD/PERADES, CHARGE, ADGC, EADI.. Lambert JC, Seshadri S, Williams J, Schellenberg GD. Novel rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nature Genetics 2017 49(9):1373-1384. PMC5669039
    3. Joshi P, Riffel F, Satoh K, Enomoto M, Qamar S, Scheiblich H, Villacampa N, Kumar S, Theil S, Parhizkar S, Haass C, Heneka MT, Fraser PE, St George-Hyslop P, Walter J. Differential interaction with TREM2 modulates microglial uptake of modified Aβ species. Glia. 2021 69(12):2917-2932. PMID: 34427354.
    4. Vilalta A, Zhou Y, Sevalle J, Griffin JK, Satoh K, Allendorf DH, De S, Puigdellívol M, Bruzas A, Burguillos MA, Dodd RB, Chen F, Zhang Y, Flagmeier P, Needham LM, Enomoto M, Qamar S, Henderson J, Walter J, Fraser PE, Klenerman D, Lee SF, St George-Hyslop P, Brown GC. Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation. J Biol Chem. 2021 296:100631. doi: 10.1016/j.jbc.2021.100631. PMID: 33823153; PMCID: PMC8113883.
  5. Cloning, Functional genomics and Structural Biology of the presenilin genes
    1. Sherrington R, Rogaev E, Liang Y, Rogaeva E, Levesque G, Ikeda MH, Chi H, Lin C, Li G, Holman K, Tsuda T, MarL, Foncin J-F, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee Y, Chumakov D, Pollen D, Tanzi RE, Wasco W, Haines JL, DaSilva R, Pericak-Vance MA, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH. Cloning of a novel gene bearing missense mutations in early onset familial Alzheimer Disease. Nature. 1995; 375: 754-760.
    2. Citron M, Westaway D, Xia W, Carlson G, Diehl TS, Seubert P, Kholodenko D, Motter R, Schenk D, Kim S, Levesque G, Sherrington R, St George-Hyslop P, and Selkoe DJ. Mutant presenilins of Alzheimer's Disease increase production of 42 residue amyloid B-protein in both transfected cells and transgenic mice. Nature Med. 1997; 3: 67-72.
    3. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song Y-Q, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang D-S, Holmes E, Milman P, Liang Y, Zhang D-M, Xu D-H, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer L, Sorbi S, Bruni AC, Fraser PE, St George-Hyslop PH. Nicastrin modulates presenilin-mediated Notch/Gip1 signal transduction and bAPP processing. Nature. 2000; 407:48-54.
    4. Li Y, Lu SH, Tsai CJ, Bohm C, Qamar S, Dodd RB, Meadows W, Jeon A, McLeod A, Chen F, Arimon M, Berezovska O, Hyman BT, Tomita T, lwatsubo T, Johnson CM, Farrer LA, Schmitt-Ulms G, Fraser PE, St George-Hyslop PH. Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes. Structure. 2014; 22(1):125-135. PMC3887256