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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Korean Society for Molecular and Cellular Biology
2019
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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. |
format | Online Article Text |
id | pubmed-6602149 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Korean Society for Molecular and Cellular Biology |
record_format | MEDLINE/PubMed |
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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