Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 17, Pages 4513-4518Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1616024114
Keywords
APC/C-Cdh1; Rock; dendrite; memory; neurodegeneration
Categories
Funding
- Instituto de Salud Carlos III [PI15/ 00473, BAE14/0005, RD12/0014/0007, RD16/0019/0018, RD12/ 0014/0001, RD16/0019/0001, PI15/00473, CP0014/00010]
- FEDER (European Regional Development Fund)
- Ministerio de Economia y Competitividad [SAF2016-78114-R]
- European Union [686009]
- Junta de Castilla y Leon (Spain)
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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/C-Cdh1 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-Cdh1-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.
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