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.; Smith, G. A.

doi:10.1038/s41420-023-01642-4

Cited by 4 publications

(1 citation statement)

References 72 publications

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“…Fly wings were imaged to examine peroxisomes in neurons according to our defined methods (Townsend et al, 2023; Maddison et al, 2023a; b; Mattedi et al, 2023). Briefly, following CO 2 anesthesia, a wing of the fly was dissected and immediately mounted in halocarbon oil between a glass slide and a coverslip for imaging using a Zeiss Axio Examiner.Z1 microscope.…”

Section: Methodsmentioning

confidence: 99%

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

Kors,

Schuster,

Maddison

et al. 2024

Preprint

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Acyl-CoA binding domain-containing proteins (ACBDs) perform diverse but often uncharacterised functions linked to cellular lipid metabolism. Human ACBD4 and ACBD5 are closely related peroxisomal membrane proteins, involved in tethering of peroxisomes to the ER and capturing fatty acids for peroxisomal β-oxidation. ACBD5 deficiency causes neurological abnormalities including ataxia and white matter disease. Peroxisome-ER contacts depend on an ACBD4/5-FFAT motif, which interacts with ER-resident VAP proteins. As ACBD4/5-like proteins are present in most fungi and all animals, we combined phylogenetic analyses with experimental approaches to improve understanding of their evolution and functions. Notably, all vertebrates exhibit gene sequences for both ACBD4 and ACBD5, while invertebrates and fungi possess only a single ACBD4/5-like protein. Our analyses revealed alterations in domain structure and FFAT sequences, which help understanding functional diversification of ACBD4/5-like proteins. We show that theDrosophila melanogasterACBD4/5-like protein possesses a functional FFAT motif to tether peroxisomes to the ER via Dm_Vap33. Depletion of Dm_Acbd4/5 caused peroxisome redistribution in wing neurons and reduced life expectancy. In contrast, the ACBD4/5-like protein of the filamentous fungusUstilago maydislacks a FFAT motif and does not interact with Um_Vap33. Loss of Um_Acbd4/5 resulted in an accumulation of peroxisomes and early endosomes at the hyphal tip. Moreover, lipid droplet numbers increased and mitochondrial membrane potential declined, implying altered lipid homeostasis. Our findings reveal differences between tethering and metabolic functions of ACBD4/5-like proteins across evolution, improving our understanding of ACBD4/5 function in health and disease. The need for a unifying nomenclature for ACBD proteins is discussed.

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Section: Methodsmentioning

confidence: 99%

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

Kors,

Schuster,

Maddison

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

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Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system

Pitolli,

Marini,

Sette

et al. 2024

Cell Death Differ

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The cyclin-dependent kinases 12 (CDK12) and 13 (CDK13) govern several steps of gene expression, including transcription, RNA processing and translation. The main target of CDK12/13 is the serine 2 residue of the carboxy-terminal domain of RNA polymerase II (RNAPII), thus influencing the directionality, elongation rate and processivity of the enzyme. The CDK12/13-dependent regulation of RNAPII activity influences the expression of selected target genes with important functional roles in the proliferation and viability of all eukaryotic cells. Neuronal cells are particularly affected by the loss of CDK12/13, as result of the high dependency of neuronal genes on RNAPII processivity for their expression. Deregulation of CDK12/13 activity strongly affects brain physiology by influencing the stemness potential and differentiation properties of neuronal precursor cells. Moreover, mounting evidence also suggest the involvement of CDK12/13 in brain tumours. Herein, we discuss the functional role(s) of CDK12 and CDK13 in gene expression regulation and highlight similarities and differences between these highly homologous kinases, with particular attention to their impact on brain physiology and pathology. Lastly, we provide an overview of CDK12/13 inhibitors and of their efficacy in brain tumours and other neoplastic diseases.

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Cyclin-dependent kinases regulate the adult nervous system via the one-carbon-metabolism

Angelin

2023

Cell Death Dis

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Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Cited by 4 publications

References 72 publications

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

New insights into the functions of ACBD4/5-like proteins using a combined phylogenetic and experimental approach across model organisms

Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system

Cyclin-dependent kinases regulate the adult nervous system via the one-carbon-metabolism

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