Research from E. Futai and co-authors provides new data about Alzheimer disease
2009 JUL 10 - (NewsRx.com) -- "gamma-Secretase is a multisubunit membrane protein complex consisting of presenilin (PS1), nicastrin (NCT), anterior pharynx-1, and presenilin enhancer 2. To analyze the activity of familial Alzheimer disease mutants and to understand the roles of the subunits, we established a yeast transcriptional activator Gal4p system with artificial gamma-secretase substrates containing amyloid precursor protein or Notch fragments. The gamma-secretase activities were evaluated by transcriptional activation of reporter genes upon Gal4p release from the membrane-bound substrates, i.e. growth of yeast on histidine and adenine, or beta-galactosidase assay," investigators in Tokyo, Japan report. "We screened and evaluated gamma-secretase mutants using this reconstitution system in yeast, which does not possess endogenous gamma-secretase activity. When we introduced familial Alzheimer mutants of PS1 in this system, their activities were shown to be loss of function. Although the protease activity of wild type PS1 depends on the other three subunits introduced, we obtained 15 new PS1 mutants, which are active in the absence of NCT. They possessed a S438P mutation at the ninth transmembrane domain (TM9) together with one missense mutation distributed through transmembrane and loop regions. These mutations were not related to familial Alzheimer mutations of PS1 as identified so far. The S438P mutant was partially active but required other mutations for full activation. Results of the beta-galactosidase assay suggested that they have wild type protease activities, which were further confirmed by the endoproteolysis of PS1, amyloid beta peptides, and Notch intracellular domain production in mammalian cells," wrote E. Futai and colleagues. The researchers concluded: "These results suggest that NCT is dispensable for the protease activity of gamma-secretase.." Futai and colleagues published their study in the Journal of Biological Chemistry (Nicastrin Is Dispensable for gamma-Secretase Protease Activity in the Presence of Specific Presenilin Mutations. Journal of Biological Chemistry, 2009;284(19):13013-13022). For additional information, contact E. Futai, 3-8-1 Komaba, Meguro Ku, Tokyo 1538902, Japan. The publisher of the Journal of Biological Chemistry can be contacted at: American Society Biochemistry Molecular Biology Inc., 9650 Rockville Pike, Bethesda, MD 20814-3996, USA. Keywords: Japan, Tokyo, Adenine, Alzheimer Disease, Biological Chemistry, Dietary Supplement, Enzyme Research, Enzymology, Galactosidase, Genetics, Genomics, Micronutrient, Protease, Reporter Gene, Secretase. This article was prepared by Genomics & Genetics Weekly editors from staff and other reports. Copyright 2009, Genomics & Genetics Weekly via NewsRx.com.
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