title: APC/CCdh1-Rock2 pathway controls dendritic integrity and memory.
abstract: Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/CCdh1substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/CCdh1-mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Bobo-Jiménez
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Delgado-Esteban
authors.affiliation: Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, 33077 Bordeaux, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Angibaud
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Sánchez-Morán
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: de la Fuente
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Yajeya
authors.affiliation: Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR 5297, 33077 Bordeaux, France.
authors.forename: U Valentin
authors.initials: UV
authors.lastname: Nägerl
authors.affiliation: Clinical Neurosciences Research Laboratory, Department of Neurology, University Hospital, Health Research Institute of Santiago de Compostela, University of Santiago de Compostela, 15706 Santiago de Compostela, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Castillo
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain.|Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain.|Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, 37007 Salamanca, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Bolaños
authors.affiliation: Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, 37007 Salamanca, Spain; aaparra@usal.es.|Institute of Functional Biology and Genomics, University of Salamanca, CSIC, 37007 Salamanca, Spain.
authors.forename: Angeles
authors.identifier: 0000-0003-0485-8904
authors.initials: A
authors.lastname: Almeida
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D064200:Cdh1 Proteins; C577585:Fzr1 protein, mouse; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D064173:Anaphase-Promoting Complex-Cyclosome; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases; C049347:fasudil
keywords: APC/CCdh1; Rock; dendrite; memory; neurodegeneration