Cyclin F can alter the turnover of TDP-43.

Autor: Rayner SL; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia. Electronic address: stephanie.rayner@mq.edu.au., Hogan A; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Davidson JM; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Chapman T; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Cheng F; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Luu L; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Wu S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Zhang S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Yang S; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Blair I; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Morsch M; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Chung R; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia., Lee A; Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health, and Human Sciences, Macquarie University, North Ryde, NSW, Australia.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Mar; Vol. 192, pp. 106421. Date of Electronic Publication: 2024 Jan 28.
DOI: 10.1016/j.nbd.2024.106421
Abstrakt: Previously, we demonstrated that the SCF cyclin 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 F MRL/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 F MRL/AAA effectively reduced the abundance of TDP-43 in cultured cells whilst cyclin F MRL/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.
Competing Interests: Declaration of competing interest Some of the data presented in this paper have been used as supporting data in a patent which has been filed by Macquarie University. SR, JD, AL and RC are co-inventors of this patent. At the time of publication, this patent is at PCT stage (Patent WO2021077162). This patent has been licensed by Celosia Therapeutics. R.C. is Chief Scientific Officer for Celosia Therapeutics.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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