Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.00016/full |
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| author | Ning-Ning Yuan Cui-Zan Cai Ming-Yue Wu Qi Zhu HuanXing Su Min Li JiaoYan Ren Jie-Qiong Tan Jia-Hong Lu |
| author_facet | Ning-Ning Yuan Cui-Zan Cai Ming-Yue Wu Qi Zhu HuanXing Su Min Li JiaoYan Ren Jie-Qiong Tan Jia-Hong Lu |
| author_sort | Ning-Ning Yuan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T07:58:42Z |
| format | Article |
| id | doaj.art-1bd14756cc3c4bef8c51cd2a28b8bb2d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T07:58:42Z |
| publishDate | 2019-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1bd14756cc3c4bef8c51cd2a28b8bb2d2022-12-22T02:55:20ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-01-011010.3389/fphar.2019.00016432000Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening TechnologyNing-Ning Yuan0Cui-Zan Cai1Ming-Yue Wu2Qi Zhu3HuanXing Su4Min Li5JiaoYan Ren6Jie-Qiong Tan7Jia-Hong Lu8State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaMr. and Mrs. Ko Chi Ming Centre for Parkinson’s Disease Research, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, ChinaSchool of Food Science and Engineering, South China University of Technology, Guangzhou, ChinaCenter for Medical Genetics, School of Life Sciences, Central South University, Changsha, ChinaState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, ChinaParkinson’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.https://www.frontiersin.org/article/10.3389/fphar.2019.00016/fullcanthin-6-oneParkinson’s diseasealpha-synucleinubiquitin-proteasome-systemCRISPR/Cas9RPN2/PSMD1 |
| spellingShingle | Ning-Ning Yuan Cui-Zan Cai Ming-Yue Wu Qi Zhu HuanXing Su Min Li JiaoYan Ren Jie-Qiong Tan Jia-Hong Lu 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 canthin-6-one Parkinson’s disease alpha-synuclein ubiquitin-proteasome-system CRISPR/Cas9 RPN2/PSMD1 |
| title | Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology |
| title_full | Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology |
| title_fullStr | Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology |
| title_full_unstemmed | Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology |
| title_short | Canthin-6-One Accelerates Alpha-Synuclein Degradation by Enhancing UPS Activity: Drug Target Identification by CRISPR-Cas9 Whole Genome-Wide Screening Technology |
| title_sort | canthin 6 one accelerates alpha synuclein degradation by enhancing ups activity drug target identification by crispr cas9 whole genome wide screening technology |
| topic | canthin-6-one Parkinson’s disease alpha-synuclein ubiquitin-proteasome-system CRISPR/Cas9 RPN2/PSMD1 |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.00016/full |
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