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NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588142/ https://www.ncbi.nlm.nih.gov/pubmed/33090185 http://dx.doi.org/10.1083/jcb.202004107 |
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author | Han, Myeong Hoon Kwon, Min Jee Ko, Byung Su Hyeon, Do Young Lee, Davin Kim, Hyung-Jun Hwang, Daehee Lee, Sung Bae |
author_facet | Han, Myeong Hoon Kwon, Min Jee Ko, Byung Su Hyeon, Do Young Lee, Davin Kim, Hyung-Jun Hwang, Daehee Lee, Sung Bae |
author_sort | Han, Myeong Hoon |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7588142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-75881422021-06-07 NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases Han, Myeong Hoon Kwon, Min Jee Ko, Byung Su Hyeon, Do Young Lee, Davin Kim, Hyung-Jun Hwang, Daehee Lee, Sung Bae J Cell Biol Article 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. Rockefeller University Press 2020-10-22 /pmc/articles/PMC7588142/ /pubmed/33090185 http://dx.doi.org/10.1083/jcb.202004107 Text en © 2020 Han et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/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/). |
spellingShingle | Article Han, Myeong Hoon Kwon, Min Jee Ko, Byung Su Hyeon, Do Young Lee, Davin Kim, Hyung-Jun Hwang, Daehee Lee, Sung Bae NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title | NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title_full | NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title_fullStr | NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title_full_unstemmed | NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title_short | NF-κB disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
title_sort | nf-κb disinhibition contributes to dendrite defects in fly models of neurodegenerative diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588142/ https://www.ncbi.nlm.nih.gov/pubmed/33090185 http://dx.doi.org/10.1083/jcb.202004107 |
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