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Título

APC/CCdh1-Rock2 pathway controls dendritic integrity and memory

AutorBobo-Jimenez, Veronica; Delgado-Esteban, María; Angibaud, Julie; Sánchez Morán, Irene; Fuente, Antonio de la; Yajeya, Javier; Nägerl, U. Valentin; Castillo, José; Bolaños, Juan P.; Almeida, Angeles
Palabras claveRock
Memory
Neurodegeneration
APC/CCdh1
Dendrite
Fecha de publicación2017
EditorNational Academy of Sciences (U.S.)
CitaciónProceedings of the National Academy of Sciences 114(17): 4513-4518 (2017)
ResumenDisruption 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 anaphasepromoting 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/C 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/C-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.
Versión del editorhttps://doi.org/10.1073/pnas.1616024114
URIhttp://hdl.handle.net/10261/157110
DOI10.1073/pnas.1616024114
Identificadoresdoi: 10.1073/pnas.1616024114
e-issn: 1091-6490
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