Genetic Mapping Studies

More than a decade ago, in collaboration with Dr. Peter St. George-Hyslop at the University of Toronto, we mapped a gene for early-onset familial AD to chromosome 14,1 which was identified in 1995 as presenilin 1. The discovery of this gene (PS1) and the protein it encodes engendered an entire “cottage industry” of scientists focused on the role of presenilins in AD pathogenesis including APP processing. More recently, we partnered again with Dr. St. George-Hyslop in a search for proteins which modulate the effect of presenilin on APP processing. This effort led to the identification of a novel protein called nicastrin (aptly named after the Italian village which is home to one of the original large extended families instrumental in the identification of PS1). Our subsequent studies determined that nicastrin is a functional component of PS1 complexes involved in the unusual intramembranous proteolytic processing of transmembrane proteins including ßAPP.2 We have also localized genes for late-onset AD in large families with multiple persons affected with AD, but the genes accounting for these linkage signals remain elusive.3-5 We expect that our current large-scale next generation sequencing studies will uncover the mutations causing AD in these families.

  1. St. George-Hyslop PH, Haines JL, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, Foncin J-F, Montesi M, Bruni A, Sorbi S, Rainero I, Piness L, Pollen   D, Polinsky R, Nee L, Kennedy J, Macciardi F, Rogaeva E, Liang Y, Alexandrova N, Lukiw W, Schlumpf K, Tanzi R, Tsuda T, Farrer LA, Cantu J-M, Duara R, Amaducci L, Bergamini L, Gusella JF, Roses A, Crapper-McLachlan DR. Genetic evidence for a novel familial Alzheimer disease locus on chromosome 14. Nature Genetics 1992; 2:330-334. PMID: 1303289
  2. Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LA, Sorbi S, Bruni A, Fraser P, St George-Hyslop P. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 2000; 407:48-54. PMID: 10993067
  3. Rogaeva E, Premkumar S, Song Y, Sorbi S, Brindle N, Psyche MRC, Paterson A, Duara R, Levesque G, Yu G, Nishimura M, Ikeda M, O’Tooke C, Kawarai T, Jorge R, Vilarino D, Bruni AC, Farrer LA, St. George-Hyslop PH. Evidence for an Alzheimer disease susceptibility locus on chromosome 12 and for further locus heterogeneity. JAMA. 1998; 280:614-618. PMID: 9718052
  4. Kunkle BW, Jaworski J, Barral S, Vardarajan B, Beecham GW, Martin ER, Cantwell LS, Partch A, Bird TD, Raskind WH, DeStefano A, Carney RM, Cantwell LS, Cuccaro, ML, Vance JM, Farrer LA, Goate AM, Foroud T, Mayeux RP, Schellenberg GD ,Haines JL, Pericak-Vance MA. Genome-wide linkage analyses of non-Hispanic White families identifies novel loci for familial late-onset Alzheimer’s disease. Alzheimers Dement 2015. In press. PMID: 26366463.
  5. Barral S, Reitz R, Vardarajan B, Cheng R, Lee J, Kunkle B, Beecham G, Cantwell LS, Pericak-Vance MA, Farrer LA, Haines JL, Schellenberg G, Mayeux R. Linkage analyses in Caribbean Hispanic families identifies novel loci associated with familial late-onset Alzheimer’s disease. Alzheimers Dement 2015.
    In press.