Deficiency of Cks1 leads to learning and long-term memory defects and p27 dependentformation of neuronal cofilin aggregates

Kukalev, Alexander, Ng, Yiu-Ming, Ju, Limei, Saidi, Amal, Lane, Sophie, Mondragon, Angeles, Dormann, Dirk, Walker, Sophie E, Grey, William, Ho, Philip Wing-Lok, Stephens, David N, Carr, Antony M, Lamsa, Karri, Tse, Eric and Yu, Veronica (2016) Deficiency of Cks1 leads to learning and long-term memory defects and p27 dependentformation of neuronal cofilin aggregates. Cerebral Cortex, 27 (1). pp. 11-23. ISSN 1047-3211

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Abstract

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.

Item Type: Article
Keywords: cyclin-dependent kinase/hippocampus/long-term potentiation/synaptic plasticity/RhoA
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Gee Wheatley
Date Deposited: 02 Nov 2016 17:05
Last Modified: 11 Sep 2017 06:10
URI: http://sro.sussex.ac.uk/id/eprint/65242

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