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

Sangwoo Ham, Hyojung Kim, Seojin Hwang, Hyunook Kang, Seung Pil Yun, Sangjune Kim, Donghoon Kim, Hyun Sook Kwon, Yun Song Lee, Myoung Lae Cho, Heung Mook Shin, Heejung Choi, Ka Young Chung, Han Seok Ko, Gum Hwa Lee, Yunjong Lee

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)480-494
Number of pages15
JournalMolecules and cells
Volume42
Issue number6
DOIs
StatePublished - Jun 30 2019

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Ham, S., Kim, H., Hwang, S., Kang, H., Yun, S. P., Kim, S., Kim, D., Kwon, H. S., Lee, Y. S., Cho, M. L., Shin, H. M., Choi, H., Chung, K. Y., Ko, H. S., Lee, G. H., & Lee, Y. (2019). Cell-Based Screen Using Amyloid Mimic β23 Expression Identifies Peucedanocoumarin III as a Novel Inhibitor of α-Synuclein and Huntingtin Aggregates. Molecules and cells, 42(6), 480-494. https://doi.org/10.14348/molcells.2019.0091