Dendrite pathology is frequently observed in various neurodegenerative diseases (NDs). Although previous studies identified several pathogenic mediators of dendrite defects that act through loss of function in NDs, the underlying pathogenic mechanisms remain largely unexplored. Here, our search for additional pathogenic contributors to dendrite defects in NDs identifies Relish/NF-κB as a novel gain-of-toxicity–based mediator of dendrite defects in animal models for polyglutamine (polyQ) diseases and amyotrophic lateral sclerosis (ALS). In a Drosophila model for polyQ diseases, polyQ-induced dendrite defects require Dredd/Caspase-8–mediated endoproteolytic cleavage of Relish to generate the N-terminal fragment, Rel68, and subsequent Charon-mediated nuclear localization of Rel68. Rel68 alone induced neuronal toxicity causing dendrite and behavioral defects, and we identify two novel transcriptional targets, Tup and Pros, that mediate Rel68-induced neuronal toxicity. Finally, we show that Rel68-induced toxicity also contributes to dendrite and behavioral defects in a Drosophila model for ALS. Collectively, our data propose disinhibition of latent toxicity of Relish/NF-κB as a novel pathogenic mechanism underlying dendrite pathology in NDs.
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7 December 2020
Article|
October 22 2020
NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases
Myeong Hoon Han,
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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Min Jee Kwon,
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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Byung Su Ko,
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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Do Young Hyeon,
Do Young Hyeon
2
School of Biological Science, Seoul National University, Seoul, Republic of Korea
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Davin Lee,
Davin Lee
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
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Hyung-Jun Kim,
Hyung-Jun Kim
3
Dementia Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
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Daehee Hwang,
Daehee Hwang
2
School of Biological Science, Seoul National University, Seoul, Republic of Korea
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Sung Bae Lee
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
4
Protein Dynamics–Based Proteotoxicity Control Laboratory, Basic Research Lab, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
5
Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
Correspondence to Sung Bae Lee: sblee@dgist.ac.kr
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Myeong Hoon Han
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
Min Jee Kwon
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
Byung Su Ko
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
Do Young Hyeon
2
School of Biological Science, Seoul National University, Seoul, Republic of Korea
Davin Lee
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
Hyung-Jun Kim
3
Dementia Research Group, Korea Brain Research Institute, Daegu, Republic of Korea
Daehee Hwang
2
School of Biological Science, Seoul National University, Seoul, Republic of Korea
Sung Bae Lee
1
Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
4
Protein Dynamics–Based Proteotoxicity Control Laboratory, Basic Research Lab, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
5
Well Aging Research Center, Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Korea
Correspondence to Sung Bae Lee: sblee@dgist.ac.kr
*
M.H. Han, M.J. Kwon, and B.S. Ko contributed equally to this paper.
Received:
April 16 2020
Revision Received:
August 18 2020
Accepted:
October 05 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
Korea Research Institute of Standards and Science
(KRISS-2019-GP2019-0018)
© 2020 Han et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2020) 219 (12): e202004107.
Article history
Received:
April 16 2020
Revision Received:
August 18 2020
Accepted:
October 05 2020
Citation
Myeong Hoon Han, Min Jee Kwon, Byung Su Ko, Do Young Hyeon, Davin Lee, Hyung-Jun Kim, Daehee Hwang, Sung Bae Lee; NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases. J Cell Biol 7 December 2020; 219 (12): e202004107. doi: https://doi.org/10.1083/jcb.202004107
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