title: Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress.
abstract: Autophagy plays a key role in the maintenance of cellular homeostasis, and autophagy deregulation gives rise to severe disorders. Many of the signaling pathways regulating autophagy under stress conditions are still poorly understood. Using a model of proteasome stress in rat hippocampus, we have characterized the functional crosstalk between the ubiquitin proteasome system and the autophagy-lysosome pathway, identifying also age-related modifications in the crosstalk between both proteolytic systems. Under proteasome inhibition, both autophagy activation and resolution were efficiently induced in young but not in aged rats, leading to restoration of protein homeostasis only in young pyramidal neurons. Importantly, proteasome stress inhibited glycogen synthase kinase-3β in young but activated in aged rats. This age-related difference could be because of a dysfunction in the signaling pathway of the insulin growth factor-1 under stress situations. Present data highlight the potential role of glycogen synthase kinase-3β in the coordination of both proteolytic systems under stress situation, representing a key molecular target to sort out this deleterious effect.
authors: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Cientíﬁcas/Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors: Elena
authors: E
authors: Gavilán
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors: Cristina
authors: C
authors: Pintado
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors: Maria P
authors: MP
authors: Gavilan
authors: Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
authors: Paula
authors: P
authors: Daza
authors: Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
authors: Inmaculada
authors: I
authors: Sánchez-Aguayo
authors: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Cientíﬁcas/Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain.
authors: Angélica
authors: A
authors: Castaño
authors: Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Cientíﬁcas/Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain. Electronic address: ruano@us.es.
authors: Diego
authors: D
authors: Ruano
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000502:physiology*; D006706:Homeostasis; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008247:Lysosomes / Q000502:physiology*; D008297:Male; D019636:Neurodegenerative Diseases / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D011506:Proteins / Q000378:metabolism; D059748:Proteolysis; D017966:Pyramidal Cells / Q000378:metabolism* / Q000502:physiology; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D025801:Ubiquitin / Q000502:physiology
chemical_list: D061988:Proteasome Inhibitors; D011506:Proteins; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
keywords: Aging; Autophagy; GSK-3β; Hippocampus; Neurodegeneration