PUBLICATION
Cyclin F can alter the turnover of TDP-43
- Authors
- Rayner, S.L., Hogan, A., Davidson, J.M., Chapman, T., Cheng, F., Luu, L., Wu, S., Zhang, S., Yang, S., Blair, I., Morsch, M., Chung, R., Lee, A.
- ID
- ZDB-PUB-240130-25
- Date
- 2024
- Source
- Neurobiology of disease 192: 106421 (Journal)
- Registered Authors
- Chung, Roger, Luu, Luan, Morsch, Marco
- Keywords
- Amyotrophic lateral sclerosis, Cyclin F, Frontotemporal dementia, TDP-43, Ubiquitylation
- MeSH Terms
-
- Amyotrophic Lateral Sclerosis*/metabolism
- Animals
- Cyclins/genetics
- Cyclins/metabolism
- DNA-Binding Proteins/metabolism
- Ubiquitination
- Zebrafish
- PubMed
- 38286389 Full text @ Neurobiol. Dis.
Citation
Rayner, S.L., Hogan, A., Davidson, J.M., Chapman, T., Cheng, F., Luu, L., Wu, S., Zhang, S., Yang, S., Blair, I., Morsch, M., Chung, R., Lee, A. (2024) Cyclin F can alter the turnover of TDP-43. Neurobiology of disease. 192:106421.
Abstract
Previously, we demonstrated that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F. To do so, we first confirmed and validated our previous findings that cyclin F binds to TDP-43 in an atypical manner. Additionally, we demonstrated that mutating the canonical substrate region in cyclin F (to generate cyclin FMRL/AAA) led to reduced binding affinity to known canonical substrates without impacting the interaction between cyclin F and TDP-43. Notably, both wild-type and cyclin FMRL/AAA effectively reduced the abundance of TDP-43 in cultured cells whilst cyclin FMRL/AAA also demonstrated reduced cell death compared to the wild-type control. The decrease in toxicity also led to a reduction in morphological defects in zebrafish embryos. These results suggest that cyclin F can be modified to enhance its targeting of TDP-43, which in turn reduces the toxicity associated with the overexpression of cyclin F. This study provides greater insights into the interaction that occurs between cyclin F and TDP-43 in cells and in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping