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LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration

Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression...

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Autores principales: Zhang, Shiqing, Xie, Jiang, Xia, Ying, Yu, Shu, Gu, Zhili, Feng, Ruili, Luo, Guanghong, Wang, Dong, Wang, Kai, Jiang, Meng, Cheng, Xiao, Huang, Hai, Zhang, Wu, Wen, Tieqiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518213/
https://www.ncbi.nlm.nih.gov/pubmed/26220523
http://dx.doi.org/10.1038/srep12564
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author Zhang, Shiqing
Xie, Jiang
Xia, Ying
Yu, Shu
Gu, Zhili
Feng, Ruili
Luo, Guanghong
Wang, Dong
Wang, Kai
Jiang, Meng
Cheng, Xiao
Huang, Hai
Zhang, Wu
Wen, Tieqiao
author_facet Zhang, Shiqing
Xie, Jiang
Xia, Ying
Yu, Shu
Gu, Zhili
Feng, Ruili
Luo, Guanghong
Wang, Dong
Wang, Kai
Jiang, Meng
Cheng, Xiao
Huang, Hai
Zhang, Wu
Wen, Tieqiao
author_sort Zhang, Shiqing
collection PubMed
description Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration.
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spelling pubmed-45182132015-08-06 LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration Zhang, Shiqing Xie, Jiang Xia, Ying Yu, Shu Gu, Zhili Feng, Ruili Luo, Guanghong Wang, Dong Wang, Kai Jiang, Meng Cheng, Xiao Huang, Hai Zhang, Wu Wen, Tieqiao Sci Rep Article Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration. Nature Publishing Group 2015-07-29 /pmc/articles/PMC4518213/ /pubmed/26220523 http://dx.doi.org/10.1038/srep12564 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Zhang, Shiqing
Xie, Jiang
Xia, Ying
Yu, Shu
Gu, Zhili
Feng, Ruili
Luo, Guanghong
Wang, Dong
Wang, Kai
Jiang, Meng
Cheng, Xiao
Huang, Hai
Zhang, Wu
Wen, Tieqiao
LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title_full LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title_fullStr LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title_full_unstemmed LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title_short LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
title_sort lk6/mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518213/
https://www.ncbi.nlm.nih.gov/pubmed/26220523
http://dx.doi.org/10.1038/srep12564
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