title: Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype.
abstract: Presenilin 1 (PSEN1) mutations are the main cause of monogenic Alzheimer's disease. We studied the functional effects of the mutation K239N, which shows incomplete penetrance at the age of 65 years and compared it with the more aggressive mutation E120G. We engineered stable cell lines expressing human PSEN1 wild type or with K239N or E120G mutations. Both mutations induced dysfunction of γ-secretase in the processing of amyloid-β protein precursor, leading to an increase in the amyloid β42/amyloid β40 ratio. Analysis of homeostatic mechanisms showed that K239N induced lower basal and hydrogen peroxide induced intracellular levels of reactive oxygen species than E120G. Similarly, K239N induced lower vulnerability to apoptosis by hydrogen peroxide injury than E120G. Accordingly, the proapoptotic signaling pathways c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase maintained PSEN1-mediated negative regulation in K239N but not in E120G-bearing cells. Furthermore, the activation of the prosurvival signaling pathways mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt was lower in E120G-bearing cells. Therefore, preservation of mechanisms regulating cell responses independent of amyloid-β protein precursor processing may account for the milder phenotype induced by the PSEN1 K239N mutation.
authors: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Barcelona, Spain.
authors: Sara
authors: S
authors: Sarroca
authors: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Barcelona, Spain.
authors: Patricia
authors: P
authors: Molina-Martínez
authors: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Barcelona, Spain.
authors: Cristina
authors: C
authors: Aresté
authors: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
authors: Martin
authors: M
authors: Etzrodt
authors: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Pablo
authors: P
authors: García de Frutos
authors: Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Rosa
authors: R
authors: Gasa
authors: Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.
authors: Anna
authors: A
authors: Antonell
authors: Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.
authors: José Luís
authors: JL
authors: Molinuevo
authors: Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain.
authors: Raquel
authors: R
authors: Sánchez-Valle
authors: Institut de Neurociències, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors: Carlos A
authors: CA
authors: Saura
authors: Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Alzheimer's Disease and Other Cognitive Disorders Unit, Department of Neurology, Hospital Clínic, Barcelona, Spain. Electronic address: allado@clinic.ub.es.
authors: Albert
authors: A
authors: Lladó
authors: Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC, Barcelona, Spain; Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: coral.sanfeliu@iibb.csic.es.
authors: Coral
authors: C
authors: Sanfeliu
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology*; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases
keywords: Akt; Amyloid-β; Apoptosis; MAP kinase signaling; Oxidative stress; Presenilin 1 mutation