Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity
Abstract Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington’s disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances t...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
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Nature Portfolio
2023-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05142-0 |
| _version_ | 1797557211774320640 |
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| author | Tien-Ying Tsai Chun-Yu Chen Tien-Wei Lin Tien-Chang Lin Feng-Lan Chiu Orion Shih Ming-Yun Chang Yu-Chun Lin An-Chung Su Chiung-Mei Chen U-Ser Jeng Hung-Chih Kuo Chi-Fon Chang Yun-Ru Chen |
| author_facet | Tien-Ying Tsai Chun-Yu Chen Tien-Wei Lin Tien-Chang Lin Feng-Lan Chiu Orion Shih Ming-Yun Chang Yu-Chun Lin An-Chung Su Chiung-Mei Chen U-Ser Jeng Hung-Chih Kuo Chi-Fon Chang Yun-Ru Chen |
| author_sort | Tien-Ying Tsai |
| collection | DOAJ |
| description | Abstract Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington’s disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances the fibrillization of and interacts with mutant thioredoxin (Trx)-fused Httex1. NMR studies with Htt peptides show that TrxHttex1-39Q interacts with the helical regions in SERF1a and SERF1a preferentially interacts with the N-terminal 17 residues of Htt. Time-course analysis shows that SERF1a induces mutant TrxHttex1 to a single conformation enriched of β-sheet. Co-expression of SERF1a and Httex1-polyQ in neuroblastoma and lentiviral infection of SERF1a in HD-induced polypotent stem cell (iPSC)-derived neurons demonstrates the detrimental effect of SERF1a in HD. Higher level of SERF1a transcript or protein is detected in HD iPSC, transgenic mice, and HD plasma. Overall, this study provides molecular mechanism for SERF1a and mutant Httex1 to facilitate therapeutic development for HD. |
| first_indexed | 2024-03-10T17:14:09Z |
| format | Article |
| id | doaj.art-6e87385b553749fe86bdfe7efeea0311 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:09Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-6e87385b553749fe86bdfe7efeea03112023-11-20T10:34:17ZengNature PortfolioCommunications Biology2399-36422023-07-016111610.1038/s42003-023-05142-0Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicityTien-Ying Tsai0Chun-Yu Chen1Tien-Wei Lin2Tien-Chang Lin3Feng-Lan Chiu4Orion Shih5Ming-Yun Chang6Yu-Chun Lin7An-Chung Su8Chiung-Mei Chen9U-Ser Jeng10Hung-Chih Kuo11Chi-Fon Chang12Yun-Ru Chen13Genomics Research Center, Academia SinicaGenomics Research Center, Academia SinicaGenomics Research Center, Academia SinicaNational Synchrotron Radiation Research CenterInstitute of Cellular and Organismic Biology, Academia SinicaNational Synchrotron Radiation Research CenterGenomics Research Center, Academia SinicaGenomics Research Center, Academia SinicaDepartment of Chemical Engineering, National Tsing Hua UniversityDepartment of Neurology, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung UniversityNational Synchrotron Radiation Research CenterInstitute of Cellular and Organismic Biology, Academia SinicaGenomics Research Center, Academia SinicaGenomics Research Center, Academia SinicaAbstract Abnormal polyglutamine (polyQ) expansion and fibrillization occur in Huntington’s disease (HD). Amyloid modifier SERF enhances amyloid formation, but the underlying mechanism is not revealed. Here, the fibrillization and toxicity effect of SERF1a on Htt-exon1 are examined. SERF1a enhances the fibrillization of and interacts with mutant thioredoxin (Trx)-fused Httex1. NMR studies with Htt peptides show that TrxHttex1-39Q interacts with the helical regions in SERF1a and SERF1a preferentially interacts with the N-terminal 17 residues of Htt. Time-course analysis shows that SERF1a induces mutant TrxHttex1 to a single conformation enriched of β-sheet. Co-expression of SERF1a and Httex1-polyQ in neuroblastoma and lentiviral infection of SERF1a in HD-induced polypotent stem cell (iPSC)-derived neurons demonstrates the detrimental effect of SERF1a in HD. Higher level of SERF1a transcript or protein is detected in HD iPSC, transgenic mice, and HD plasma. Overall, this study provides molecular mechanism for SERF1a and mutant Httex1 to facilitate therapeutic development for HD.https://doi.org/10.1038/s42003-023-05142-0 |
| spellingShingle | Tien-Ying Tsai Chun-Yu Chen Tien-Wei Lin Tien-Chang Lin Feng-Lan Chiu Orion Shih Ming-Yun Chang Yu-Chun Lin An-Chung Su Chiung-Mei Chen U-Ser Jeng Hung-Chih Kuo Chi-Fon Chang Yun-Ru Chen Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity Communications Biology |
| title | Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity |
| title_full | Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity |
| title_fullStr | Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity |
| title_full_unstemmed | Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity |
| title_short | Amyloid modifier SERF1a interacts with polyQ-expanded huntingtin-exon 1 via helical interactions and exacerbates polyQ-induced toxicity |
| title_sort | amyloid modifier serf1a interacts with polyq expanded huntingtin exon 1 via helical interactions and exacerbates polyq induced toxicity |
| url | https://doi.org/10.1038/s42003-023-05142-0 |
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