Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids
Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids
Abstract 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.
Winderickx Joris、Wu Xiang、Zhao Lei、Jin Xuejiao、Hao Xinxin、Chen Lihua、Liu Beidong、Liu Shenkui、Zheng Ju、Cao Xiuling
Functional BiologyState Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityDepartment of Chemistry and Molecular Biology, University of GothenburgState Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityDepartment of Chemistry and Molecular Biology, University of GothenburgDepartment of Chemistry and Molecular Biology, University of Gothenburg||Guangzhou LaboratoryState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University||Department of Chemistry and Molecular Biology, University of GothenburgState Key Laboratory of Subtropical Silviculture, Zhejiang A&F UniversityDepartment of Chemistry and Molecular Biology, University of Gothenburg||Functional BiologyState Key Laboratory of Subtropical Silviculture, Zhejiang A&F University||Department of Chemistry and Molecular Biology, University of Gothenburg
基础医学生物科学研究方法、生物科学研究技术分子生物学
Winderickx Joris,Wu Xiang,Zhao Lei,Jin Xuejiao,Hao Xinxin,Chen Lihua,Liu Beidong,Liu Shenkui,Zheng Ju,Cao Xiuling.Maturation and detoxification of synphilin-1 inclusion bodies regulated by sphingolipids[EB/OL].(2025-03-28)[2025-05-28].https://www.biorxiv.org/content/10.1101/2023.09.27.559647.点此复制
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