Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids
Due to proteostasis stress induced by aging or disease, misfolded proteins can form toxic intermediate species of aggregates and eventually mature into less toxic inclusion bodies (IBs). Here, using a yeast imaging-based screen, we identified 84 potential synphilin-1 (SY1) IB regulators and isolated...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/92180 |
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| author | Xiuling Cao Xiang Wu Lei Zhao Ju Zheng Xuejiao Jin Xinxin Hao Joris Winderickx Shenkui Liu Lihua Chen Beidong Liu |
| author_facet | Xiuling Cao Xiang Wu Lei Zhao Ju Zheng Xuejiao Jin Xinxin Hao Joris Winderickx Shenkui Liu Lihua Chen Beidong Liu |
| author_sort | Xiuling Cao |
| collection | DOAJ |
| description | Due to proteostasis stress induced by aging or disease, misfolded proteins can form toxic intermediate species of aggregates and eventually mature into less toxic inclusion bodies (IBs). Here, using a yeast imaging-based screen, we identified 84 potential synphilin-1 (SY1) IB regulators and isolated the conserved sphingolipid metabolic components in the most enriched groups. Furthermore, we show that, in both yeast cells and mammalian cells, SY1 IBs are associated with mitochondria. Pharmacological inhibition of the sphingolipid metabolism pathway or knockout of its key genes results in a delayed IB maturation and increased SY1 cytotoxicity. We postulate that SY1 IB matures by association with the mitochondrion membrane, and that sphingolipids stimulate the maturation via their membrane-modulating function and thereby protecting cells from SY1 cytotoxicity. Our findings identify a conserved cellular component essential for IB maturation and suggest a mechanism by which cells may detoxify the pathogenic protein aggregates through forming mitochondrion-associated IBs. |
| format | Article |
| id | doaj-art-127b4aa837f24430a33ce632db5b3d41 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-127b4aa837f24430a33ce632db5b3d412025-02-10T13:02:53ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011210.7554/eLife.92180Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipidsXiuling Cao0https://orcid.org/0000-0001-6940-4482Xiang Wu1Lei Zhao2Ju Zheng3Xuejiao Jin4Xinxin Hao5Joris Winderickx6https://orcid.org/0000-0003-3133-7733Shenkui Liu7Lihua Chen8https://orcid.org/0000-0003-3369-1875Beidong Liu9https://orcid.org/0000-0001-6052-8411State Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, China; Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, ChinaDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; Functional Biology, KU Leuven, Leuven, BelgiumState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, ChinaDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenFunctional Biology, KU Leuven, Leuven, BelgiumState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, ChinaDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden; Guangzhou National Laboratory, Guangzhou, Guangdong, ChinaState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University, Hangzhou, China; Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenDue to proteostasis stress induced by aging or disease, misfolded proteins can form toxic intermediate species of aggregates and eventually mature into less toxic inclusion bodies (IBs). Here, using a yeast imaging-based screen, we identified 84 potential synphilin-1 (SY1) IB regulators and isolated the conserved sphingolipid metabolic components in the most enriched groups. Furthermore, we show that, in both yeast cells and mammalian cells, SY1 IBs are associated with mitochondria. Pharmacological inhibition of the sphingolipid metabolism pathway or knockout of its key genes results in a delayed IB maturation and increased SY1 cytotoxicity. We postulate that SY1 IB matures by association with the mitochondrion membrane, and that sphingolipids stimulate the maturation via their membrane-modulating function and thereby protecting cells from SY1 cytotoxicity. Our findings identify a conserved cellular component essential for IB maturation and suggest a mechanism by which cells may detoxify the pathogenic protein aggregates through forming mitochondrion-associated IBs.https://elifesciences.org/articles/92180synphilin-1sphingolipidsinclusion bodiesimaging-based screenmitochondrionmammalian cells |
| spellingShingle | Xiuling Cao Xiang Wu Lei Zhao Ju Zheng Xuejiao Jin Xinxin Hao Joris Winderickx Shenkui Liu Lihua Chen Beidong Liu Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids eLife synphilin-1 sphingolipids inclusion bodies imaging-based screen mitochondrion mammalian cells |
| title | Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids |
| title_full | Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids |
| title_fullStr | Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids |
| title_full_unstemmed | Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids |
| title_short | Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids |
| title_sort | maturation and detoxification of synphilin 1 inclusion bodies regulated by sphingolipids |
| topic | synphilin-1 sphingolipids inclusion bodies imaging-based screen mitochondrion mammalian cells |
| url | https://elifesciences.org/articles/92180 |
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