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Mol Cells. 2019 Jun 30;42(6):480-494. doi: 10.14348/molcells.2019.0091.

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

Ham S1, Kim H1, Hwang S2, Kang H3, Yun SP4,5,6, Kim S4,5,6, Kim D4,5,6, Kwon HS7, Lee YS1, Cho M7, Shin HM7, Choi H3, Chung KY8, Ko HS4,5,6, Lee GH2, Lee Y1,9.

Author information

1
Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
2
College of Pharmacy, Chosun University, Gwangju 61452, Korea.
3
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
4
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering.
5
Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
6
Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA.
7
National Development Institute of Korean Medicine, Gyeongsan 38540, Korea.
8
School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea.
9
Samsung Medical Center, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Seoul 06351, Korea.

Abstract

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. Highthroughput 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.

KEYWORDS:

Tet-Off model; amyloid; fibril; natural compound screen; neurodegenerative disease; peucedanocoumarin III; α-synuclein

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