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E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway
Genetic studies have revealed that rare mutations and multiplications of the gene locus in α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson’s disease (PD). However, the pathological effects of α-syn are still obscure. The neurotoxicity of α-syn is mainly determined by its protein...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278282/ https://www.ncbi.nlm.nih.gov/pubmed/30388770 http://dx.doi.org/10.3390/molecules23112839 |
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author | Yan, Jia-qing Yuan, Yu-he Chu, Shi-feng Li, Guo-hui Chen, Nai-hong |
author_facet | Yan, Jia-qing Yuan, Yu-he Chu, Shi-feng Li, Guo-hui Chen, Nai-hong |
author_sort | Yan, Jia-qing |
collection | PubMed |
description | Genetic studies have revealed that rare mutations and multiplications of the gene locus in α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson’s disease (PD). However, the pathological effects of α-syn are still obscure. The neurotoxicity of α-syn is mainly determined by its protein levels, which depend on a balance between synthesis and degradation. Therefore, verifying the possible routes contributing to the clearance of α-syn is important for PD therapy. In this study, we established stable lines overexpressing human wild-type (WT) and E46K mutant α-syn in rat PC12 cells and investigated the degradation pathways of α-syn by using a panel of inhibitors and inducers of lysosome and proteasome function. We also monitored the degradation kinetics of α-syn by using cycloheximide to block protein synthesis. Our data showed that both proteasome and chaperon-mediated autophagy (CMA) are responsible for the degradation of the WT α-syn. Meanwhile, E46K mutant α-syn is mainly degraded by the proteasome and macroautophagy pathway. Compared with the WT protein, E46K mutant α-syn turned over more slowly in PC12 cells. In addition, overexpression of E46K mutant α-syn increased vulnerability of PC12 cells to apoptosis insults when compared with WT α-syn. Our findings may verify the possible routes contributing to the degradation of the E46K mutant α-syn. |
format | Online Article Text |
id | pubmed-6278282 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-62782822018-12-13 E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway Yan, Jia-qing Yuan, Yu-he Chu, Shi-feng Li, Guo-hui Chen, Nai-hong Molecules Article Genetic studies have revealed that rare mutations and multiplications of the gene locus in α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson’s disease (PD). However, the pathological effects of α-syn are still obscure. The neurotoxicity of α-syn is mainly determined by its protein levels, which depend on a balance between synthesis and degradation. Therefore, verifying the possible routes contributing to the clearance of α-syn is important for PD therapy. In this study, we established stable lines overexpressing human wild-type (WT) and E46K mutant α-syn in rat PC12 cells and investigated the degradation pathways of α-syn by using a panel of inhibitors and inducers of lysosome and proteasome function. We also monitored the degradation kinetics of α-syn by using cycloheximide to block protein synthesis. Our data showed that both proteasome and chaperon-mediated autophagy (CMA) are responsible for the degradation of the WT α-syn. Meanwhile, E46K mutant α-syn is mainly degraded by the proteasome and macroautophagy pathway. Compared with the WT protein, E46K mutant α-syn turned over more slowly in PC12 cells. In addition, overexpression of E46K mutant α-syn increased vulnerability of PC12 cells to apoptosis insults when compared with WT α-syn. Our findings may verify the possible routes contributing to the degradation of the E46K mutant α-syn. MDPI 2018-11-01 /pmc/articles/PMC6278282/ /pubmed/30388770 http://dx.doi.org/10.3390/molecules23112839 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Yan, Jia-qing Yuan, Yu-he Chu, Shi-feng Li, Guo-hui Chen, Nai-hong E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title | E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title_full | E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title_fullStr | E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title_full_unstemmed | E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title_short | E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway |
title_sort | e46k mutant α-synuclein is degraded by both proteasome and macroautophagy pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278282/ https://www.ncbi.nlm.nih.gov/pubmed/30388770 http://dx.doi.org/10.3390/molecules23112839 |
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