APC/CCdh1-Rock2 pathway controls dendritic integrity and memory
Proc Natl Acad Sci USA. 2017-04-10; 114(17): 4513-4518
DOI: 10.1073/pnas.1616024114
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1. Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4513-4518. doi:
10.1073/pnas.1616024114. Epub 2017 Apr 10.
APC/CCdh1-Rock2 pathway controls dendritic integrity and memory.
Bobo-Jiménez V(1)(2), Delgado-Esteban M(1)(2), Angibaud J(3), Sánchez-Morán
I(1)(2), de la Fuente A(4), Yajeya J(4), Nägerl UV(3), Castillo J(5), Bolaños
JP(1)(2)(6), Almeida A(7)(2).
Author information:
(1)Institute of Biomedical Research of Salamanca, University Hospital of
Salamanca, University of Salamanca, Consejo Superior de Investigaciones
Científicas, 37007 Salamanca, Spain.
(2)Institute of Functional Biology and Genomics, University of Salamanca, CSIC,
37007 Salamanca, Spain.
(3)Interdisciplinary Institute for Neuroscience, University of Bordeaux, CNRS UMR
5297, 33077 Bordeaux, France.
(4)Department of Physiology and Pharmacology, Faculty of Medicine, University of
Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain.
(5)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.
(6)Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento
Saludable, 37007 Salamanca, Spain.
(7)Institute of Biomedical Research of Salamanca, University Hospital of
Salamanca, University of Salamanca, Consejo Superior de Investigaciones
Científicas, 37007 Salamanca, Spain; .
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/CCdh1 substrate 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.
DOI: 10.1073/pnas.1616024114
PMCID: PMC5410848
PMID: 28396402 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest.