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Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology
Ning-Ning Yuan1; Cui-Zan Cai1; Ming-Yue Wu1; Qi Zhu1; HuanXing Su1; Min Li2; JiaoYan Ren3; Jie-Qiong Tan4; Jia-Hong Lu1
2019-01
Source PublicationFRONTIERS IN PHARMACOLOGY
ISSN1663-9812
Other Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the ubiquitin-proteasome system has been linked to its accumulation. In this work, we developed a tetracycline–inducible expression system, with simultaneous induced expression of α-syn-EGFP and a bright red fluorescent protein marker (mCherry) to screen for potential compounds for degrading α-syn. We identified canthin-6-one as an α-syn lowering compound which promoted both wild type and mutants α-syn degradation in an ubiquitin-proteasome-system (UPS) dependent manner. By CRISPR/Cas9 genome-wide screening technology, we identified RPN2/PSMD1, the 26S proteasome non-ATPase regulatory subunit 1, as the targeting gene for pharmacological activity of canthin-6-one. Finally, we showed that canthin-6-one up-regulates PSMD1 and enhances UPS function by activating PKA.

KeywordCanthin-6-one Parkinson’s Disease Alpha-synuclein Ubiquitin-proteasome-system Crispr/cas9 Rpn2/psmd1 Pka
DOI10.3389/fphar.2019.00016
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000456925900001
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Cited Times [WOS]:3   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorJia-Hong Lu
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau,Macao, China
2.Mr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine,Hong Kong Baptist University, Hong Kong, China
3.School of Food Science and Engineering, South China Universityof Technology, Guangzhou, China
4.Center for Medical Genetics, School of Life Sciences, Central South University,Changsha, China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Ning-Ning Yuan,Cui-Zan Cai,Ming-Yue Wu,et al. Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology[J]. FRONTIERS IN PHARMACOLOGY,2019.
APA Ning-Ning Yuan.,Cui-Zan Cai.,Ming-Yue Wu.,Qi Zhu.,HuanXing Su.,...&Jia-Hong Lu.(2019).Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology.FRONTIERS IN PHARMACOLOGY.
MLA Ning-Ning Yuan,et al."Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology".FRONTIERS IN PHARMACOLOGY (2019).
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