Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation.
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...
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183076&type=printable |
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| author | Xiang-Jun Sheng Hunag-Ju Tu Wei-Lin Chien Kai-Hsiang Kang Dai-Hua Lu Horng-Huei Liou Ming-Jen Lee Wen-Mei Fu |
| author_facet | Xiang-Jun Sheng Hunag-Ju Tu Wei-Lin Chien Kai-Hsiang Kang Dai-Hua Lu Horng-Huei Liou Ming-Jen Lee Wen-Mei Fu |
| author_sort | Xiang-Jun Sheng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2b458dba7db445929088c22ae9f9e500 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-2b458dba7db445929088c22ae9f9e5002025-08-20T02:04:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01128e018307610.1371/journal.pone.0183076Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation.Xiang-Jun ShengHunag-Ju TuWei-Lin ChienKai-Hsiang KangDai-Hua LuHorng-Huei LiouMing-Jen LeeWen-Mei FuPTEN-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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183076&type=printable |
| spellingShingle | Xiang-Jun Sheng Hunag-Ju Tu Wei-Lin Chien Kai-Hsiang Kang Dai-Hua Lu Horng-Huei Liou Ming-Jen Lee Wen-Mei Fu Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. PLoS ONE |
| title | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. |
| title_full | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. |
| title_fullStr | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. |
| title_full_unstemmed | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. |
| title_short | Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. |
| title_sort | antagonism of proteasome inhibitor induced heme oxygenase 1 expression by pink1 mutation |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0183076&type=printable |
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