Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Townsend, L. N., Clarke, H., Maddison, D., Jones, K. M., Amadio, L., Jefferson, A., Chughtai, U., Bis, D. M., Züchner, S., Allen, N. D., Van der Goes van Naters, W., Peters, O. M. and Smith, G. A. ORCID: https://orcid.org/0000-0003-4332-8383 2023. Cdk12 maintains the integrity of adult axons by suppressing actin remodeling. Cell Death Discovery 9 (1) , 348. 10.1038/s41420-023-01642-4

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Abstract

The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer’s disease and we provide a candidate molecular pathway to link together such pathological events.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Springer Nature
ISSN:	2058-7716
Funders:	MRC, Wellcome Trust
Date of First Compliant Deposit:	25 September 2023
Date of Acceptance:	7 September 2023
Last Modified:	31 Oct 2023 10:05
URI:	https://orca.cardiff.ac.uk/id/eprint/162713

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