Cargando…

Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway

Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Da, Shi, Ji-Jun, Mao, Cheng-Jie, Liu, Sha, Wang, Jian-Da, Chen, Jing, Wang, Fen, Yang, Ya-Ping, Hu, Wei-Dong, Hu, Li-Fang, Liu, Chun-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Molecular Diversity Preservation International (MDPI) 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876108/
https://www.ncbi.nlm.nih.gov/pubmed/24351814
http://dx.doi.org/10.3390/ijms141224242
_version_ 1782297471188205568
author Li, Da
Shi, Ji-Jun
Mao, Cheng-Jie
Liu, Sha
Wang, Jian-Da
Chen, Jing
Wang, Fen
Yang, Ya-Ping
Hu, Wei-Dong
Hu, Li-Fang
Liu, Chun-Feng
author_facet Li, Da
Shi, Ji-Jun
Mao, Cheng-Jie
Liu, Sha
Wang, Jian-Da
Chen, Jing
Wang, Fen
Yang, Ya-Ping
Hu, Wei-Dong
Hu, Li-Fang
Liu, Chun-Feng
author_sort Li, Da
collection PubMed
description Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of misfolded proteins and damaged organells. Previous studies reported that dynein dysfuntion was associated with aberrant aggregation of α-synuclein, which is a major component of inclusion bodies in Parkinson’s disease (PD). However, it remains unclear what roles dynein plays in α-synuclein degradation. Our study demonstrated a decrease of dynein expression in neurotoxin-induced PD models in vitro and in vivo, accompanied by an increase of α-synuclein protein level. Dynein down-regulation induced by siRNA resulted in a prolonged half-life of α-synuclein and its over-accumulation in A53T overexpressing PC12 cells. Dynein knockdown also prompted the increase of microtubule-associated protein 1 light chain 3 (LC3-II) and sequestosome 1 (SQSTM1, p62) expression, and the accumulation of autophagic vacuoles. Moreover, dynein suppression impaired the autophagosome fusion with lysosome. In summary, our findings indicate that dynein is critical for the clearance of aberrant α-synuclein via autophagosome-lysosome pathway.
format Online
Article
Text
id pubmed-3876108
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Molecular Diversity Preservation International (MDPI)
record_format MEDLINE/PubMed
spelling pubmed-38761082013-12-31 Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway Li, Da Shi, Ji-Jun Mao, Cheng-Jie Liu, Sha Wang, Jian-Da Chen, Jing Wang, Fen Yang, Ya-Ping Hu, Wei-Dong Hu, Li-Fang Liu, Chun-Feng Int J Mol Sci Article Growing evidence suggests that dynein dysfunction may be implicated in the pathogenesis of neurodegeneration. It plays a central role in aggresome formation, the delivery of autophagosome to lysosome for fusion and degradation, which is a pro-survival mechanism essential for the bulk degradation of misfolded proteins and damaged organells. Previous studies reported that dynein dysfuntion was associated with aberrant aggregation of α-synuclein, which is a major component of inclusion bodies in Parkinson’s disease (PD). However, it remains unclear what roles dynein plays in α-synuclein degradation. Our study demonstrated a decrease of dynein expression in neurotoxin-induced PD models in vitro and in vivo, accompanied by an increase of α-synuclein protein level. Dynein down-regulation induced by siRNA resulted in a prolonged half-life of α-synuclein and its over-accumulation in A53T overexpressing PC12 cells. Dynein knockdown also prompted the increase of microtubule-associated protein 1 light chain 3 (LC3-II) and sequestosome 1 (SQSTM1, p62) expression, and the accumulation of autophagic vacuoles. Moreover, dynein suppression impaired the autophagosome fusion with lysosome. In summary, our findings indicate that dynein is critical for the clearance of aberrant α-synuclein via autophagosome-lysosome pathway. Molecular Diversity Preservation International (MDPI) 2013-12-13 /pmc/articles/PMC3876108/ /pubmed/24351814 http://dx.doi.org/10.3390/ijms141224242 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Li, Da
Shi, Ji-Jun
Mao, Cheng-Jie
Liu, Sha
Wang, Jian-Da
Chen, Jing
Wang, Fen
Yang, Ya-Ping
Hu, Wei-Dong
Hu, Li-Fang
Liu, Chun-Feng
Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title_full Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title_fullStr Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title_full_unstemmed Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title_short Alteration of Dynein Function Affects α-Synuclein Degradation via the Autophagosome-Lysosome Pathway
title_sort alteration of dynein function affects α-synuclein degradation via the autophagosome-lysosome pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876108/
https://www.ncbi.nlm.nih.gov/pubmed/24351814
http://dx.doi.org/10.3390/ijms141224242
work_keys_str_mv AT lida alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT shijijun alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT maochengjie alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT liusha alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT wangjianda alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT chenjing alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT wangfen alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT yangyaping alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT huweidong alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT hulifang alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway
AT liuchunfeng alterationofdyneinfunctionaffectsasynucleindegradationviatheautophagosomelysosomepathway