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Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates

Aggregates of disease-causing proteins dysregulate cellular functions, thereby causing neuronal cell loss in diverse neurodegenerative diseases. Although many in vitro or in vivo studies of protein aggregate inhibitors have been performed, a therapeutic strategy to control aggregate toxicity has not...

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Autores principales: Ham, Sangwoo, Kim, Hyojung, Hwang, Seojin, Kang, Hyunook, Yun, Seung Pil, Kim, Sangjune, Kim, Donghoon, Kwon, Hyun Sook, Lee, Yun-Song, Cho, MyoungLae, Shin, Heung-Mook, Choi, Heejung, Chung, Ka Young, Ko, Han Seok, Lee, Gum Hwa, Lee, Yunjong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Korean Society for Molecular and Cellular Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602149/
https://www.ncbi.nlm.nih.gov/pubmed/31250621
http://dx.doi.org/10.14348/molcells.2019.0091
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author Ham, Sangwoo
Kim, Hyojung
Hwang, Seojin
Kang, Hyunook
Yun, Seung Pil
Kim, Sangjune
Kim, Donghoon
Kwon, Hyun Sook
Lee, Yun-Song
Cho, MyoungLae
Shin, Heung-Mook
Choi, Heejung
Chung, Ka Young
Ko, Han Seok
Lee, Gum Hwa
Lee, Yunjong
author_facet Ham, Sangwoo
Kim, Hyojung
Hwang, Seojin
Kang, Hyunook
Yun, Seung Pil
Kim, Sangjune
Kim, Donghoon
Kwon, Hyun Sook
Lee, Yun-Song
Cho, MyoungLae
Shin, Heung-Mook
Choi, Heejung
Chung, Ka Young
Ko, Han Seok
Lee, Gum Hwa
Lee, Yunjong
author_sort Ham, Sangwoo
collection PubMed
description Aggregates of disease-causing proteins dysregulate cellular functions, thereby causing neuronal cell loss in diverse neurodegenerative diseases. Although many in vitro or in vivo studies of protein aggregate inhibitors have been performed, a therapeutic strategy to control aggregate toxicity has not been earnestly pursued, partly due to the limitations of available aggregate models. In this study, we established a tetracycline (Tet)-inducible nuclear aggregate (β23) expression model to screen potential lead compounds inhibiting β23-induced toxicity. High-throughput screening identified several natural compounds as nuclear β23 inhibitors, including peucedanocoumarin III (PCIII). Interestingly, PCIII accelerates disaggregation and proteasomal clearance of both nuclear and cytosolic β23 aggregates and protects SH-SY5Y cells from toxicity induced by β23 expression. Of translational relevance, PCIII disassembled fibrils and enhanced clearance of cytosolic and nuclear protein aggregates in cellular models of huntingtin and α-synuclein aggregation. Moreover, cellular toxicity was diminished with PCIII treatment for polyglutamine (PolyQ)-huntingtin expression and α-synuclein expression in conjunction with 6-hydroxydopamine (6-OHDA) treatment. Importantly, PCIII not only inhibited α-synuclein aggregation but also disaggregated preformed α-synuclein fibrils in vitro. Taken together, our results suggest that a Tet-Off β23 cell model could serve as a robust platform for screening effective lead compounds inhibiting nuclear or cytosolic protein aggregates. Brain-permeable PCIII or its derivatives could be beneficial for eliminating established protein aggregates.
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spelling pubmed-66021492019-07-10 Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates Ham, Sangwoo Kim, Hyojung Hwang, Seojin Kang, Hyunook Yun, Seung Pil Kim, Sangjune Kim, Donghoon Kwon, Hyun Sook Lee, Yun-Song Cho, MyoungLae Shin, Heung-Mook Choi, Heejung Chung, Ka Young Ko, Han Seok Lee, Gum Hwa Lee, Yunjong Mol Cells Articles Aggregates of disease-causing proteins dysregulate cellular functions, thereby causing neuronal cell loss in diverse neurodegenerative diseases. Although many in vitro or in vivo studies of protein aggregate inhibitors have been performed, a therapeutic strategy to control aggregate toxicity has not been earnestly pursued, partly due to the limitations of available aggregate models. In this study, we established a tetracycline (Tet)-inducible nuclear aggregate (β23) expression model to screen potential lead compounds inhibiting β23-induced toxicity. High-throughput screening identified several natural compounds as nuclear β23 inhibitors, including peucedanocoumarin III (PCIII). Interestingly, PCIII accelerates disaggregation and proteasomal clearance of both nuclear and cytosolic β23 aggregates and protects SH-SY5Y cells from toxicity induced by β23 expression. Of translational relevance, PCIII disassembled fibrils and enhanced clearance of cytosolic and nuclear protein aggregates in cellular models of huntingtin and α-synuclein aggregation. Moreover, cellular toxicity was diminished with PCIII treatment for polyglutamine (PolyQ)-huntingtin expression and α-synuclein expression in conjunction with 6-hydroxydopamine (6-OHDA) treatment. Importantly, PCIII not only inhibited α-synuclein aggregation but also disaggregated preformed α-synuclein fibrils in vitro. Taken together, our results suggest that a Tet-Off β23 cell model could serve as a robust platform for screening effective lead compounds inhibiting nuclear or cytosolic protein aggregates. Brain-permeable PCIII or its derivatives could be beneficial for eliminating established protein aggregates. Korean Society for Molecular and Cellular Biology 2019-06 2019-06-15 /pmc/articles/PMC6602149/ /pubmed/31250621 http://dx.doi.org/10.14348/molcells.2019.0091 Text en © The Korean Society for Molecular and Cellular Biology. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
spellingShingle Articles
Ham, Sangwoo
Kim, Hyojung
Hwang, Seojin
Kang, Hyunook
Yun, Seung Pil
Kim, Sangjune
Kim, Donghoon
Kwon, Hyun Sook
Lee, Yun-Song
Cho, MyoungLae
Shin, Heung-Mook
Choi, Heejung
Chung, Ka Young
Ko, Han Seok
Lee, Gum Hwa
Lee, Yunjong
Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title_full Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title_fullStr Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title_full_unstemmed Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title_short Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates
title_sort cell-based screen using amyloid mimic β23 expression identifies peucedanocoumarin iii as a novel inhibitor of α-synuclein and huntingtin aggregates
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602149/
https://www.ncbi.nlm.nih.gov/pubmed/31250621
http://dx.doi.org/10.14348/molcells.2019.0091
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