Cyclin F can alter the turnover of TDP-43.
Neurobiol Dis
; 192: 106421, 2024 Mar.
Article
in En
| MEDLINE
| ID: mdl-38286389
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyotrophic Lateral Sclerosis
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Neurobiol Dis
Journal subject:
NEUROLOGIA
Year:
2024
Document type:
Article