Cyclin F can alter the turnover of TDP-43

被引:0
|
作者
Rayner, Stephanie L. [1 ,2 ]
Hogan, Alison [1 ]
Davidson, Jennilee M. [1 ]
Chapman, Tyler [1 ]
Cheng, Flora [1 ]
Luu, Luan [1 ]
Wu, Sharlynn [1 ]
Zhang, Selina [1 ]
Yang, Shu [1 ]
Blair, Ian [1 ]
Morsch, Marco [1 ]
Chung, Roger [1 ]
Lee, Albert [1 ]
机构
[1] Macquarie Univ, Fac Med Hlth & Human Sci, Motor Neuron Dis Res Ctr, Macquarie Med Sch, N Ryde, NSW, Australia
[2] Macquarie Univ, Macquarie Med Sch, 2 Technol Pl, Sydney, NSW 2109, Australia
关键词
Amyotrophic lateral sclerosis; Frontotemporal dementia; Cyclin F; TDP-43; Ubiquitylation; FRONTOTEMPORAL LOBAR DEGENERATION; NEURODEGENERATION; INCLUSIONS; EXPRESSION; COMPONENT;
D O I
10.1016/j.nbd.2024.106421
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
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页数:10
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