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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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