The grant detail shows the name of the PI, active dates of the project, the funding institute and the abstract of the grant. This abstract is what is used to create the fingerprint of the grant. If any publications referencing this grant are found in the data, they will be listed here as well.
Gamma Secretases in Alzheimers Disease
10 April 2000 - 30 April 2009
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Total Funding: $ 2,532,291
Gamma-secretase catalyzes the final cleavage that releases ABeta from its precursor; therefore, it is a potential therapeutic target for the treatment of AD. A great deal of evidence now supports the concept that presenilins (PS) are catalytic components of the high molecular weight gamma-secretase complex. We have identified a novel family of presenilin homologues (PSH). PSH can be aligned over most of their lengths with PS. Regions that are highly conserved between the two families include i) putative active site aspartate residues in TMD6 and TMD7, ii) TMD sequences in general, and iii) a 'PAL' motif that is reported to be obligatory for stabilization, complex formation, and gamma-secretase activities of PS. One of the PSH has now been shown to be an intramembrane cleaving protease. Based on this evidence we hypothesize that that PS and PSH represent a family of intramembraneous cleaving proteases with a conserved catalytic mechanism. As shown for other enzyme families, the identification of a wider repertoire of PS/PSH family members may now facilitate a greater understanding of the molecular and cellular functions of this biomedically-important family. Given the interest in developing gamma-secretase inhibitors that target PS as potential therapeutic agents, information gathered by studying this protein family may offer important insights into the potential catalytic mechanisms and substrate-specificities of PS and PSH that will aid the development of such inhibitors. These studies will also provide general insight as to how intramembrane cleavage of peptide bonds occurs. The questions we will address are 1) What are the basic characteristics and cellular roles of the PSH proteins? 2) Do PSs and PSHs utilize a catalytic mechanism similar to that known of other aspartyl proteases? 3) What are the structural similarities between the active sites of PSH and PS? Do PSHs possess an initial substrate docking site as PS apparently does? And 4) Does SPP/PSH3 indeed act alone (and as a dimer)?
15 Resulting Publications
Todd E Golde; Leonard Petrucelli; Jada LewisExperimental neurology 2010;223(2):252-66.
Todd E Golde; Michael S Wolfe; Doron C GreenbaumSeminars in cell & developmental biology 2009;20(2):225-30.
Andrew C Nyborg; Thomas B Ladd; Karen Jansen; Thomas Kukar; Todd E GoldeFASEB journal : official publication of the Federation of American Societies for Experimental Biology 2006;20(10):1671-9.
Jun Wang; Dirk Beher; Andrew C Nyborg; Mark S Shearman; Todd E Golde; Alison GoateJournal of neurochemistry 2006;96(1):218-27.
Andrew C Nyborg; Karen Jansen; Thomas B Ladd; Abdul Fauq; Todd E Golde
A signal peptide peptidase (SPP) reporter activity assay based on the cleavage of type II membrane protein substrates provides further evidence for an inverted orientation of the SPP active site relative to presenilin.The Journal of biological chemistry 2004;279(41):43148-56.
Andrew C Nyborg; Anna Y Kornilova; Karen Jansen; Thomas B Ladd; Michael S Wolfe; Todd E GoldeThe Journal of biological chemistry 2004;279(15):15153-60.
M Ramsden; A C Nyborg; M P Murphy; L Chang; F Z Stanczyk; T E Golde; C J PikeJournal of neurochemistry 2003;87(4):1052-5.
Bruno Martoglio; Todd E GoldeHuman molecular genetics 2003;12 Spec No 2():R201-6.
Siân C Piper; Zareen Amtul; Laura Galiñanes-Garcia; Victor G Howard; Chewki Ziani-Cherif; Chris McLendon; Marjorie J Rochette; Abdul Fauq; Todd E Golde; M Paul MurphyBiochemical and biophysical research communications 2003;305(3):529-33.
Malcolm A Leissring; M Paul Murphy; Tonya R Mead; Yama Akbari; Michael C Sugarman; Mehrdad Jannatipour; Brigitte Anliker; Ulrike Müller; Paul Saftig; Bart De Strooper; et al.Proceedings of the National Academy of Sciences of the United States of America 2002;99(7):4697-702.
M Paul Murphy; Sacha N Uljon; Todd E Golde; Rong WangBiochimica et biophysica acta 2002;1586(2):199-209.
Zareen Amtul; Patrick A Lewis; Sian Piper; Richard Crook; Matt Baker; Kirk Findlay; Andrew Singleton; Marion Hogg; Linda Younkin; Steven G Younkin; et al.Neurobiology of disease 2002;9(2):269-73.
Suzanne Wahrle; Pritam Das; Andrew C Nyborg; Chris McLendon; Mikio Shoji; Takeshi Kawarabayashi; Linda H Younkin; Steven G Younkin; Todd E GoldeNeurobiology of disease 2002;9(1):11-23.
C Y Ni; M P Murphy; T E Golde; G CarpenterScience (New York, N.Y.) 2001;294(5549):2179-81.
P A Lewis; S Piper; M Baker; L Onstead; M P Murphy; J Hardy; R Wang; E McGowan; T E GoldeBiochimica et biophysica acta 2001;1537(1):58-62.
This section shows information that has been computed by using the fingerprint of the grant, including related publications, related experts and related grants - all with fingerprints representing significant amounts of overlap between their fingerprint and this grant. The red dots indicate whether those experts or terms actually appear within this grant, showing potential and actual connections.
Goate, Alison M
1 July 2005 - 30 June 2008
FOGARTY INTERNATIONAL CENTER
Total Funding: $ 117,923
Gandy, Samuel E
1 September 2005 - 30 June 2008
NATIONAL INSTITUTE ON AGING
Total Funding: $ 898,167
GANDY, SAMUEL E
15 September 1996 - 31 March 1998
NATIONAL INSTITUTE ON AGING
Total Funding: $ 502,038
Isabell Greeve; Doris Kretzschmar; Jakob-Andreas Tschäpe; Anika Beyn; Claire Brellinger; Michaela Schweizer; Roger M Nitsch; Rita ReifegersteThe Journal of neuroscience : the official journal of the Society for Neuroscience 2004;24(16):3899-906.
M P Murphy; R Wang; P E Fraser; A Fauq; T E GoldeAnnals of the New York Academy of Sciences 2000;920():233-40.
J Nunan; M S Shearman; F Checler; R Cappai; G Evin; K Beyreuther; C L Masters; D H SmallEuropean journal of biochemistry / FEBS 2001;268(20):5329-36.
Appears in this Publication
Author of this Publication