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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...

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Autores principales: Yan, Jia-qing, Yuan, Yu-he, Chu, Shi-feng, Li, Guo-hui, Chen, Nai-hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
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.
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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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