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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...

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Autores principales: Han, Myeong Hoon, Kwon, Min Jee, Ko, Byung Su, Hyeon, Do Young, Lee, Davin, Kim, Hyung-Jun, Hwang, Daehee, Lee, Sung Bae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
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.
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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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