title: Reduced Aph-1b expression causes tissue- and substrate-specific changes in gamma-secretase activity in rats with a complex phenotype.
abstract: The gamma-secretase enzyme complex displays intramembrane catalytic activity toward many type I transmembrane proteins, including the Alzheimer-linked amyloid-beta-protein precursor (APP) and the neuregulin receptor ErbB4. Active gamma-secretase is a tetrameric protein complex consisting of presenilin-1 (or -2), nicastrin, PEN-2, and Aph-1a (or -1b). We have recently discovered that pharmacogenetically bred apomorphine-susceptible Wistar rats (APO-SUS) have only one or two copies of the Aph-1b gene (termed I/I and II/II rats, respectively), whereas their phenotypic counterparts (APO-UNSUS) have three copies (III/III). As a result, APO-SUS rats display reduced Aph-1b expression and a complex phenotype reminiscent of neurodevelopmental disorders. Here we determined in the I/I and III/III rats the gamma-secretase cleavage activity toward the three APP superfamily members, p75 neurotrophin receptor, ErbB4, and neuregulin-2, and found that the cleavage of only a subset of the substrates was changed. Furthermore, the observed differences were restricted to tissues that normally express relatively high Aph-1b compared with Aph-1a levels. Thus, we provide in vivo evidence that subtle alterations in gamma-secretase subunit composition may lead to a variety of affected (neuro)developmental signaling pathways and, consequently, a complex phenotype.
authors.affiliation: Department of Molecular Animal Physiology-Nijmegen Center for Molecular Life Sciences (NCMLS) and Institute for Neuroscience-Radboud University of Nijmegen, The Netherlands.
authors.forename: Marcel W
authors.initials: MW
authors.lastname: Coolen
authors.forename: Karen M J
authors.initials: KM
authors.lastname: van Loo
authors.forename: Nick N H M
authors.initials: NN
authors.lastname: van Bakel
authors.forename: Bart A
authors.initials: BA
authors.lastname: Ellenbroek
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Cools
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Martens
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D001058:Apomorphine; D001522:Behavior, Animal; D010450:Endopeptidases / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013379:Substrate Specificity
chemical_list: C508903:Aph-1 protein, rat; D008565:Membrane Proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D001058:Apomorphine