KMID : 0578320190420060480
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Molecules and Cells 2019 Volume.42 No. 6 p.480 ~ p.494
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Cell-Based Screen Using Amyloid Mimic ¥â23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of ¥á-Synuclein and Huntingtin Aggregates
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Ham Sang-Woo
Kim Hyo-Jung Hwang Seo-Jin Kang Hyun-Ook Yun Seung-Pil Kim Sang-June Kim Dong-Hoon Kwon Hyun-Sook Lee Yun-Song Cho Myoung-Lae Shin Heung-Mook Choi Hee-Jung Chung Ka-Young Ko Han-Seok Lee Gum-Hwa Lee Yun-Jong
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Abstract
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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 (¥â23) expression model to screen potential lead compounds inhibiting ¥â23-induced toxicity. High-throughput screening identified several natural compounds as nuclear ¥â23 inhibitors, including peucedanocoumarin III (PCIII). Interestingly, PCIII accelerates disaggregation and proteasomal clearance of both nuclear and cytosolic ¥â23 aggregates and protects SH-SY5Y cells from toxicity induced by ¥â23 expression. Of translational relevance, PCIII disassembled fibrils and enhanced clearance of cytosolic and nuclear protein aggregates in cellular models of huntingtin and ¥á-synuclein aggregation. Moreover, cellular toxicity was diminished with PCIII treatment for polyglutamine (PolyQ)-huntingtin expression and ¥á-synuclein expression in conjunction with 6-hydroxydopamine (6-OHDA) treatment. Importantly, PCIII not only inhibited ¥á-synuclein aggregation but also disaggregated preformed ¥á-synuclein fibrils in vitro. Taken together, our results suggest that a Tet-Off ¥â23 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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KEYWORD
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¥á-synuclein, amyloid, fibril, natural compound screen, neurodegenerative disease, peucedanocoumarin III, Tet-Off model
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