USP14 is crucial for proteostasis regulation and α-synuclein degradation in human SH-SY5Y dopaminergic cells
Vignesh Srinivasan,
Rabah Soliymani,
Larisa Ivanova,
Ove Eriksson,
Nina Peitsaro,
Maciej Lalowski,
Mati Karelson,
Dan Lindholm
Affiliations
Vignesh Srinivasan
Department 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
Rabah Soliymani
Department 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
Larisa Ivanova
Institute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, Estonia
Ove Eriksson
Department 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
Nina Peitsaro
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FIN-00014, Finland
Maciej Lalowski
Department 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, Poland
Mati Karelson
Institute of Chemistry, University of Tartu, Ravila 14a, 50411, Tartu, Estonia
Dan Lindholm
Department 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.
