Piperine ameliorates SCA17 neuropathology by reducing ER stress
Abstract Background Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cere...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-018-0236-x |
| _version_ | 1819066990089732096 |
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| author | Jifeng Guo Yiting Cui Qiong Liu Yang Yang Yujing Li Ling Weng Beisha Tang Peng Jin Xiao-Jiang Li Su Yang Shihua Li |
| author_facet | Jifeng Guo Yiting Cui Qiong Liu Yang Yang Yujing Li Ling Weng Beisha Tang Peng Jin Xiao-Jiang Li Su Yang Shihua Li |
| author_sort | Jifeng Guo |
| collection | DOAJ |
| description | Abstract Background Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17. Methods In this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression. Results Addition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress. Conclusion Our study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17. |
| first_indexed | 2024-12-21T16:11:08Z |
| format | Article |
| id | doaj.art-12dbe738657345839a0ccc245a56dc16 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T16:11:08Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-12dbe738657345839a0ccc245a56dc162022-12-21T18:57:47ZengBMCMolecular Neurodegeneration1750-13262018-01-0113111310.1186/s13024-018-0236-xPiperine ameliorates SCA17 neuropathology by reducing ER stressJifeng Guo0Yiting Cui1Qiong Liu2Yang Yang3Yujing Li4Ling Weng5Beisha Tang6Peng Jin7Xiao-Jiang Li8Su Yang9Shihua Li10Department of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Human Genetics, Emory University School of MedicineDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityDepartment of Human Genetics, Emory University School of MedicineDepartment of Human Genetics, Emory University School of MedicineDepartment of Human Genetics, Emory University School of MedicineDepartment of Neurology and National Clinical Research Center for Geriatric Disorder, Xiangya Hospital, Central South UniversityAbstract Background Spinocerebellar ataxia 17 (SCA17) belongs to the family of neurodegenerative diseases caused by polyglutamine (polyQ) expansion. In SCA17, polyQ expansion occurs in the TATA box binding protein (TBP) and leads to the misfolding of TBP and the preferential degeneration in the cerebellar Purkinje neurons. Currently there is no effective treatment for SCA17. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a recently identified neurotrophic factor, and increasing MANF expression ameliorated SCA17 neuropathology in TBP-105Q knock-in (KI) mouse model, indicating that MANF could be a therapeutic target for treating SCA17. Methods In this study, we screened a collection of 2000 FDA-approved chemicals using a stable cell line expressing luciferase reporter, which is driven by MANF promoter. We identified several potential candidates that can induce the expression of MANF. Of these inducers, piperine is an agent that potently induces the luciferase expression or MANF expression. Results Addition of piperine in both cellular and mouse models of SCA17 alleviated toxicity caused by mutant TBP. Although mutant TBP is primarily localized in the nuclei, the polyQ expansion in TBP is able to induce ER stress, suggesting that nuclear misfolded proteins can also elicit ER stress as cytoplasmic misfolded proteins do. Moreover, piperine plays its protective role by reducing toxicity caused by the ER stress. Conclusion Our study established piperine as a MANF-based therapeutic agent for ER stress-related neuropathology in SCA17.http://link.springer.com/article/10.1186/s13024-018-0236-xPolyglutamineAtaxiaNeurotrophic factorER stress |
| spellingShingle | Jifeng Guo Yiting Cui Qiong Liu Yang Yang Yujing Li Ling Weng Beisha Tang Peng Jin Xiao-Jiang Li Su Yang Shihua Li Piperine ameliorates SCA17 neuropathology by reducing ER stress Molecular Neurodegeneration Polyglutamine Ataxia Neurotrophic factor ER stress |
| title | Piperine ameliorates SCA17 neuropathology by reducing ER stress |
| title_full | Piperine ameliorates SCA17 neuropathology by reducing ER stress |
| title_fullStr | Piperine ameliorates SCA17 neuropathology by reducing ER stress |
| title_full_unstemmed | Piperine ameliorates SCA17 neuropathology by reducing ER stress |
| title_short | Piperine ameliorates SCA17 neuropathology by reducing ER stress |
| title_sort | piperine ameliorates sca17 neuropathology by reducing er stress |
| topic | Polyglutamine Ataxia Neurotrophic factor ER stress |
| url | http://link.springer.com/article/10.1186/s13024-018-0236-x |
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