Cdk12 maintains the integrity of adult axons by suppressing actin remodeling
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 negat...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-09-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01642-4 |
| _version_ | 1827635552831143936 |
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| author | L. N. Townsend H. Clarke D. Maddison K. M. Jones L. Amadio A. Jefferson U. Chughtai D. M. Bis S. Züchner N. D. Allen W. Van der Goes van Naters O. M. Peters G. A. Smith |
| author_facet | L. N. Townsend H. Clarke D. Maddison K. M. Jones L. Amadio A. Jefferson U. Chughtai D. M. Bis S. Züchner N. D. Allen W. Van der Goes van Naters O. M. Peters G. A. Smith |
| author_sort | L. N. Townsend |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:29:16Z |
| format | Article |
| id | doaj.art-63985a4ff92040e99788aac4b613a346 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-09T15:29:16Z |
| publishDate | 2023-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-63985a4ff92040e99788aac4b613a3462023-11-26T12:21:38ZengNature Publishing GroupCell Death Discovery2058-77162023-09-019111210.1038/s41420-023-01642-4Cdk12 maintains the integrity of adult axons by suppressing actin remodelingL. N. Townsend0H. Clarke1D. Maddison2K. M. Jones3L. Amadio4A. Jefferson5U. Chughtai6D. M. Bis7S. Züchner8N. D. Allen9W. Van der Goes van Naters10O. M. Peters11G. A. Smith12School of Biosciences, Cardiff UniversitySchool of Medicine, Cardiff UniversitySchool of Medicine, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Medicine, Cardiff UniversitySchool of Biosciences, Cardiff UniversityJohn P. Hussman Institute for Human Genomics, University of MiamiJohn P. Hussman Institute for Human Genomics, University of MiamiSchool of Biosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Biosciences, Cardiff UniversitySchool of Medicine, Cardiff UniversityAbstract 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.https://doi.org/10.1038/s41420-023-01642-4 |
| spellingShingle | L. N. Townsend H. Clarke D. Maddison K. M. Jones L. Amadio A. Jefferson U. Chughtai D. M. Bis S. Züchner N. D. Allen W. Van der Goes van Naters O. M. Peters G. A. Smith Cdk12 maintains the integrity of adult axons by suppressing actin remodeling Cell Death Discovery |
| title | Cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| title_full | Cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| title_fullStr | Cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| title_full_unstemmed | Cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| title_short | Cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| title_sort | cdk12 maintains the integrity of adult axons by suppressing actin remodeling |
| url | https://doi.org/10.1038/s41420-023-01642-4 |
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