Cdk12 maintains the integrity of adult axons by suppressing actin remodeling.
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
20 Sep 2023
20 Sep 2023
Historique:
received:
10
05
2023
accepted:
07
09
2023
revised:
25
08
2023
medline:
21
9
2023
pubmed:
21
9
2023
entrez:
20
9
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37730761
doi: 10.1038/s41420-023-01642-4
pii: 10.1038/s41420-023-01642-4
pmc: PMC10511712
doi:
Types de publication
Journal Article
Langues
eng
Pagination
348Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_16030/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W004879/1
Pays : United Kingdom
Informations de copyright
© 2023. Cell Death Differentiation Association (ADMC).
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