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

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Version 1 2023-06-09, 03:52
journal contribution
posted on 2023-06-12, 08:33 authored by 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 CarrAntony Carr, Karri Lamsa, Eric Tse, Veronica Yu
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Cerebral Cortex

ISSN

1047-3211

Publisher

Oxford University Press

Issue

1

Volume

27

Page range

11-23

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2016-11-02

First Open Access (FOA) Date

2017-02-23

First Compliant Deposit (FCD) Date

2016-11-02

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