Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation
<p>Abstract</p> <p>Background</p> <p>Accumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emergin...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2011-05-01
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| Series: | Molecular Neurodegeneration |
| Online Access: | http://www.molecularneurodegeneration.com/content/6/1/34 |
| _version_ | 1818363435294916608 |
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| author | Ma Yuliang Reicher Joshua Wu Wei Kabakoff Jonathan Shi Yang Yao Dongdong Meng Fanjun Moosmann Bernd Masliah Eliezer Lipton Stuart A Gu Zezong |
| author_facet | Ma Yuliang Reicher Joshua Wu Wei Kabakoff Jonathan Shi Yang Yao Dongdong Meng Fanjun Moosmann Bernd Masliah Eliezer Lipton Stuart A Gu Zezong |
| author_sort | Ma Yuliang |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Accumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emerging evidence suggests that oxidative/nitrosative stress compromises the precisely-regulated network of ubiquitination in PD, particularly affecting parkin E3 ligase activity, and contributes to the accumulation of toxic proteins and neuronal cell death.</p> <p>Results</p> <p>To gain insight into the mechanism whereby cell stress alters parkin-mediated ubiquitination and LB formation, we investigated the effect of oxidative stress. We found significant increases in oxidation (sulfonation) and subsequent aggregation of parkin in SH-SY5Y cells exposed to the mitochondrial complex I inhibitor 1-methyl-4-phenlypyridinium (MPP<sup><b>+</b></sup>), representing an <it>in vitro </it>cell-based PD model. Exposure of these cells to direct oxidation via pathological doses of H<sub>2</sub>O<sub>2 </sub>induced a vicious cycle of increased followed by decreased parkin E3 ligase activity, similar to that previously reported following S-nitrosylation of parkin. Pre-incubation with catalase attenuated H<sub>2</sub>O<sub>2 </sub>accumulation, parkin sulfonation, and parkin aggregation. Mass spectrometry (MS) analysis revealed that H<sub>2</sub>O<sub>2 </sub>reacted with specific cysteine residues of parkin, resulting in sulfination/sulfonation in regions of the protein similar to those affected by parkin mutations in hereditary forms of PD. Immunohistochemistry or gel electrophoresis revealed an increase in aggregated parkin in rats and primates exposed to mitochondrial complex I inhibitors, as well as in postmortem human brain from patients with PD with LBs.</p> <p>Conclusion</p> <p>These findings show that oxidative stress alters parkin E3 ligase activity, leading to dysfunction of the ubiquitin-proteasome system and potentially contributing to LB formation.</p> |
| first_indexed | 2024-12-13T21:48:26Z |
| format | Article |
| id | doaj.art-6bacdf0214c549e48fc7f4b51686fb0b |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-13T21:48:26Z |
| publishDate | 2011-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-6bacdf0214c549e48fc7f4b51686fb0b2022-12-21T23:30:20ZengBMCMolecular Neurodegeneration1750-13262011-05-01613410.1186/1750-1326-6-34Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregationMa YuliangReicher JoshuaWu WeiKabakoff JonathanShi YangYao DongdongMeng FanjunMoosmann BerndMasliah EliezerLipton Stuart AGu Zezong<p>Abstract</p> <p>Background</p> <p>Accumulation of aberrant proteins to form Lewy bodies (LBs) is a hallmark of Parkinson's disease (PD). Ubiquitination-mediated degradation of aberrant, misfolded proteins is critical for maintaining normal cell function. Emerging evidence suggests that oxidative/nitrosative stress compromises the precisely-regulated network of ubiquitination in PD, particularly affecting parkin E3 ligase activity, and contributes to the accumulation of toxic proteins and neuronal cell death.</p> <p>Results</p> <p>To gain insight into the mechanism whereby cell stress alters parkin-mediated ubiquitination and LB formation, we investigated the effect of oxidative stress. We found significant increases in oxidation (sulfonation) and subsequent aggregation of parkin in SH-SY5Y cells exposed to the mitochondrial complex I inhibitor 1-methyl-4-phenlypyridinium (MPP<sup><b>+</b></sup>), representing an <it>in vitro </it>cell-based PD model. Exposure of these cells to direct oxidation via pathological doses of H<sub>2</sub>O<sub>2 </sub>induced a vicious cycle of increased followed by decreased parkin E3 ligase activity, similar to that previously reported following S-nitrosylation of parkin. Pre-incubation with catalase attenuated H<sub>2</sub>O<sub>2 </sub>accumulation, parkin sulfonation, and parkin aggregation. Mass spectrometry (MS) analysis revealed that H<sub>2</sub>O<sub>2 </sub>reacted with specific cysteine residues of parkin, resulting in sulfination/sulfonation in regions of the protein similar to those affected by parkin mutations in hereditary forms of PD. Immunohistochemistry or gel electrophoresis revealed an increase in aggregated parkin in rats and primates exposed to mitochondrial complex I inhibitors, as well as in postmortem human brain from patients with PD with LBs.</p> <p>Conclusion</p> <p>These findings show that oxidative stress alters parkin E3 ligase activity, leading to dysfunction of the ubiquitin-proteasome system and potentially contributing to LB formation.</p>http://www.molecularneurodegeneration.com/content/6/1/34 |
| spellingShingle | Ma Yuliang Reicher Joshua Wu Wei Kabakoff Jonathan Shi Yang Yao Dongdong Meng Fanjun Moosmann Bernd Masliah Eliezer Lipton Stuart A Gu Zezong Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation Molecular Neurodegeneration |
| title | Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation |
| title_full | Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation |
| title_fullStr | Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation |
| title_full_unstemmed | Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation |
| title_short | Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation |
| title_sort | oxidation of the cysteine rich regions of parkin perturbs its e3 ligase activity and contributes to protein aggregation |
| url | http://www.molecularneurodegeneration.com/content/6/1/34 |
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