Deficiency of Cks1 Leads to Learning and Long-Term Memory Defects and p27 Dependent Formation of Neuronal Cofilin Aggregates
| Autor: | Alexander, Kukalev, Yiu-Ming, Ng, Limei, Ju, Amal, Saidi, Sophie, Lane, Angeles, Mondragon, Dirk, Dormann, Sophie E, Walker, William, Grey, Philip Wing-Lok, Ho, David N, Stephens, Antony M, Carr, Karri, Lamsa, Eric, Tse, Veronica P C C, Yu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Mice Knockout Neurons Memory Disorders Memory Long-Term synaptic plasticity hippocampus Dendritic Spines Cell Cycle Long-Term Potentiation Spatial Learning RhoA macromolecular substances Original Articles environment and public health Mice Protein Aggregates cyclin-dependent kinase Actin Depolymerizing Factors CDC2-CDC28 Kinases Animals Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Cerebral Cortex (New York, NY) |
| ISSN: | 1460-2199 |
| Popis: | In mitotic cells, the cyclin-dependent kinase (CDK) subunit protein CKS1 regulates S phase entry by mediating degradation of the CDK inhibitor p27. Although mature neurons lack mitotic CDKs, we found that CKS1 was actively expressed in post-mitotic neurons of the adult hippocampus. Interestingly, Cks1 knockout (Cks1−/−) mice exhibited poor long-term memory, and diminished maintenance of long-term potentiation in the hippocampal circuits. Furthermore, there was neuronal accumulation of cofilin-actin rods or cofilin aggregates, which are associated with defective dendritic spine maturation and synaptic loss. We further demonstrated that it was the increased p27 level that activated cofilin by suppressing the RhoA kinase-mediated inhibitory phosphorylation of cofilin, resulting in the formation of cofilin aggregates in the Cks1−/− neuronal cells. Consistent with reports that the peptidyl-prolyl-isomerase PIN1 competes with CKS1 for p27 binding, we found that inhibition of PIN1 diminished the formation of cofilin aggregates through decreasing p27 levels, thereby activating RhoA and increasing cofilin phosphorylation. Our results revealed that CKS1 is involved in normal glutamatergic synapse development and dendritic spine maturation in adult hippocampus through modulating p27 stability. |
| Databáze: | OpenAIRE |
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