APC/CCdh1-Rock2 pathway controls dendritic integrity and memory

Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4513-4518. doi: 10.1073/pnas.1616024114. Epub 2017 Apr 10.


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.

Keywords: APC/CCdh1; Rock; dendrite; memory; neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Anaphase-Promoting Complex-Cyclosome / genetics
  • Anaphase-Promoting Complex-Cyclosome / metabolism*
  • Animals
  • Cdh1 Proteins / genetics
  • Cdh1 Proteins / metabolism*
  • Cell Survival
  • Dendritic Cells / physiology*
  • Gene Expression Regulation / physiology*
  • Memory / drug effects
  • Memory / physiology
  • Mice
  • Mice, Knockout
  • Neurons / physiology
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*


  • Cdh1 Proteins
  • Fzr1 protein, mouse
  • Protein Kinase Inhibitors
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Anaphase-Promoting Complex-Cyclosome
  • Rock2 protein, mouse
  • rho-Associated Kinases
  • fasudil