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.
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/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.
神经元形态的破坏导致神经退行性疾病（如阿尔茨海默病）的病理学发生。然而，其潜在的分子机制尚不清楚。在这里，我们表明，神经元中细胞分裂后期促进复合物/细胞周期蛋白（APC/C）泛素连接酶的辅助因子 Cdh1 的出生后缺失（Cdh1 条件敲除（cKO））破坏树突分支，导致皮质和海马中的树突棘和突触丢失，同时伴有记忆障碍和神经退行性变。我们发现，树突不稳定性 Rho 蛋白激酶 2（Rock2），其在 AD 患者的大脑中积累，是体内 APC/C 的底物，并且 Rock2 蛋白和活性在 Cdh1 cKO 小鼠的皮质和海马中增加。在这些动物中，使用临床批准的药物法舒地尔抑制 Rock 活性可防止树突网络紊乱、记忆丧失和神经退行性变。因此，APC/C 介导的 Rock2 降解维持树突网络、记忆形成和神经元存活，表明异常积累的 Rock2 的药理学抑制可能是治疗神经退行性变的合适治疗策略。
