https://scholars.lib.ntu.edu.tw/handle/123456789/519120
標題: | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation | 作者: | Sheng X.-J. Tu H.-J. Chien W.-L. Kang K.-H. Lu D.-H. HORNG-HUEI LIOU MING-JEN LEE WEN-MEI FU |
公開日期: | 2017 | 出版社: | Public Library of Science | 卷: | 12 | 期: | 8 | 起(迄)頁: | e0183076 | 來源出版物: | PLoS ONE | 摘要: | PTEN-induced putative kinase 1 (PINK1) is an integral protein in the mitochondrial membrane and maintains mitochondrial fidelity. Pathogenic mutations in PINK1 have been identified as a cause of early-onset autosomal recessive familial Parkinson’s disease (PD). The ubiquitin proteasome pathway is associated with neurodegenerative diseases. In this study, we investigated whether mutations of PINK1 affects the cellular stress response following proteasome inhibition. Administration of MG132, a peptide aldehyde proteasome inhibitor, significantly increased the expression of heme oxygenase-1 (HO-1) in rat dopaminergic neurons in the substantia nigra and in the SH-SY5Y neuronal cell line. The induction of HO-1 expression by proteasome inhibition was reduced in PINK1 G309D mutant cells. MG132 increased the levels of HO-1 through the Akt, p38, and Nrf2 signaling pathways. Compared with the cells expressing WT-PINK1, the phosphorylation of Akt and p38 was lower in those cells expressing the PINK1 G309D mutant, which resulted in the inhibition of the nuclear translocation of Nrf2. Furthermore, MG132-induced neuronal death was enhanced by the PINK1 G309D mutation. In this study, we demonstrated that the G309D mutation impairs the neuroprotective function of PINK1 following proteasome inhibition, which may be related to the pathogenesis of PD. ? 2017 Sheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028568243&doi=10.1371%2fjournal.pone.0183076&partnerID=40&md5=43b096f6d14c6721533b30d6a9488204 https://scholars.lib.ntu.edu.tw/handle/123456789/519120 |
DOI: | 10.1371/journal.pone.0183076 | SDG/關鍵字: | benzyloxycarbonylleucylleucylleucinal; heme oxygenase 1; kelch like ECH associated protein 1; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proteasome; protein kinase B; protein PINK1; small interfering RNA; synaptophysin; transcription factor Nrf2; unclassified drug; benzyloxycarbonylleucyl-leucyl-leucine aldehyde; heme oxygenase 1; leupeptin; mutant protein; proteasome inhibitor; protein kinase; PTEN-induced putative kinase; transcription factor Nrf2; animal experiment; animal model; Article; cell count; cell nucleus; cell survival; cell viability; cellular stress response; controlled study; cytoplasm; dopaminergic nerve cell; enzyme activity; enzyme inhibition; human; human cell; nerve cell; nonhuman; Parkinson disease; pathogenesis; protein expression; protein function; protein localization; protein phosphorylation; rat; substantia nigra; upregulation; animal; antioxidant responsive element; biological model; cell death; cell line; drug effects; gene expression regulation; genetic transfection; genetics; male; metabolism; mutation; protein transport; signal transduction; Wistar rat; Animals; Antioxidant Response Elements; Cell Death; Cell Line; Cell Nucleus; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Leupeptins; Male; Models, Biological; Mutant Proteins; Mutation; Neurons; NF-E2-Related Factor 2; Proteasome Inhibitors; Protein Kinases; Protein Transport; Rats, Wistar; Signal Transduction; Substantia Nigra; Transfection; Up-Regulation |
顯示於: | 醫學系 |
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