title: The pathogenic L392V mutation of presenilin 1 decreases the affinity to glycogen synthase kinase-3 beta.
abstract: Determination of the effects of presenilin 1 (PSEN1) mutations, involved in autosomal dominant early-onset Alzheimer's disease (ADEOAD), on the interaction between PSEN1 and binding proteins is essential to determine which interactions are involved in Alzheimer's disease (AD) pathogenesis. The PSEN1 binding protein glycogen synthase kinase-3 beta (GSK-3 beta) has been considered as a key protein in AD pathogenesis since GSK-3 beta phosphorylates tau and hyperphosphorylated tau is a main component of neurofibrillary tangles associated to AD. We show here, using surface plasmonic resonance, that the pathogenic L392V mutation, identified in a large French ADEOAD pedigree including 39 affected members, leads to a decreased affinity to GSK-3 beta. We conclude therefore that the increase of affinity of PSEN1 to GSK-3 beta reported in previous studies is not a common effect of pathogenic mutations associated to ADEOAD.
authors.affiliation: INSERM EPI 9906, Faculté mixte de Médecine et de Pharmacie, 76183 Rouen Cedex, IFRMP, 76821 Mont Saint-Aignan, Cedex, France.
authors.forename: R
authors.initials: R
authors.lastname: Gantier
authors.forename: D
authors.initials: D
authors.lastname: Gilbert
authors.forename: C
authors.initials: C
authors.lastname: Dumanchin
authors.forename: D
authors.initials: D
authors.lastname: Campion
authors.forename: D
authors.initials: D
authors.lastname: Davoust
authors.forename: F
authors.initials: F
authors.lastname: Toma
authors.forename: T
authors.initials: T
authors.lastname: Frébourg
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D019943:Amino Acid Substitution / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007930:Leucine / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1; D011485:Protein Binding / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D020349:Surface Plasmon Resonance; D014633:Valine / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011994:Recombinant Proteins; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007930:Leucine; D014633:Valine