USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells
Ubiquitin specific protease-14 (USP14) is critical for controlling proteostasis disturbed in human disorders, including Parkinson's disease (PD). Here we investigated USP14 in the regulation of α-synuclein (α-syn) degradation via the proteasome and autophagy. α-Syn and pS129 α-syn were elevated...
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Elsevier
2025-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025004116 |
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| author | Vignesh Srinivasan Rabah Soliymani Larisa Ivanova Ove Eriksson Nina Peitsaro Maciej Lalowski Mati Karelson Dan Lindholm |
| author_facet | Vignesh Srinivasan Rabah Soliymani Larisa Ivanova Ove Eriksson Nina Peitsaro Maciej Lalowski Mati Karelson Dan Lindholm |
| author_sort | Vignesh Srinivasan |
| collection | DOAJ |
| description | Ubiquitin specific protease-14 (USP14) is critical for controlling proteostasis disturbed in human disorders, including Parkinson's disease (PD). Here we investigated USP14 in the regulation of α-synuclein (α-syn) degradation via the proteasome and autophagy. α-Syn and pS129 α-syn were elevated in USP14 gene-deleted SH-SY5Y dopaminergic cells with decreased proteasome activity. However, autophagy and coordinated lysosomal expression and regulation pathways were elevated in USP14 lacking cells with higher levels of the transcription factor TFEB. There was an increase in reactive oxidative species (ROS) and elongated mitochondria in USP14 deficient cells and counteracting oxidative stress decreased α-syn levels. Phosphoproteomics revealed that USP14 is phosphorylated at residue S143 that reduces its binding to the proteasome. Re-expression of wild-type and phospho-mimetic S143D-USP14 mutant lowered ROS and α-syn levels in USP14 lacking cells. USP14 is a promising factor to consider in PD to target α-syn through its regulation of proteasomes and oxidative stress in dopaminergic neurons. |
| format | Article |
| id | doaj-art-33f5772ff9f84d308c4bcc36ccd561c9 |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-33f5772ff9f84d308c4bcc36ccd561c92025-01-27T04:22:03ZengElsevierHeliyon2405-84402025-02-01113e42031USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cellsVignesh Srinivasan0Rabah Soliymani1Larisa Ivanova2Ove Eriksson3Nina Peitsaro4Maciej Lalowski5Mati Karelson6Dan Lindholm7Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, FinlandDepartment of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland; HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, FinlandInstitute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, EstoniaDepartment of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, FinlandDepartment of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, FinlandDepartment of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland; HiLIFE, Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland; Institute of Molecular Biology and Biochemistry, Department of Gene Expression, Faculty of Biology, Adam Mickiewicz University, Poznań, PolandInstitute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, EstoniaDepartment of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Corresponding author. Department of Biochemistry and Developmental Biology, University of Helsinki, Finland.Ubiquitin specific protease-14 (USP14) is critical for controlling proteostasis disturbed in human disorders, including Parkinson's disease (PD). Here we investigated USP14 in the regulation of α-synuclein (α-syn) degradation via the proteasome and autophagy. α-Syn and pS129 α-syn were elevated in USP14 gene-deleted SH-SY5Y dopaminergic cells with decreased proteasome activity. However, autophagy and coordinated lysosomal expression and regulation pathways were elevated in USP14 lacking cells with higher levels of the transcription factor TFEB. There was an increase in reactive oxidative species (ROS) and elongated mitochondria in USP14 deficient cells and counteracting oxidative stress decreased α-syn levels. Phosphoproteomics revealed that USP14 is phosphorylated at residue S143 that reduces its binding to the proteasome. Re-expression of wild-type and phospho-mimetic S143D-USP14 mutant lowered ROS and α-syn levels in USP14 lacking cells. USP14 is a promising factor to consider in PD to target α-syn through its regulation of proteasomes and oxidative stress in dopaminergic neurons.http://www.sciencedirect.com/science/article/pii/S2405844025004116USP14Proteasomeα-SynucleinpS129 α-SynucleinOxidative stressAutophagy |
| spellingShingle | Vignesh Srinivasan Rabah Soliymani Larisa Ivanova Ove Eriksson Nina Peitsaro Maciej Lalowski Mati Karelson Dan Lindholm USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells Heliyon USP14 Proteasome α-Synuclein pS129 α-Synuclein Oxidative stress Autophagy |
| title | USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells |
| title_full | USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells |
| title_fullStr | USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells |
| title_full_unstemmed | USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells |
| title_short | USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells |
| title_sort | usp14 is crucial for proteostasis regulation and α synuclein degradation in human sh sy5y dopaminergic cells |
| topic | USP14 Proteasome α-Synuclein pS129 α-Synuclein Oxidative stress Autophagy |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025004116 |
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