Unfolded protein response and activated degradative pathways regulation in GNE myopathy.

Although intracellular beta amyloid (Aβ) accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have no...

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Autores principales:	Honghao Li, Qi Chen, Fuchen Liu, Xuemei Zhang, Wei Li, Shuping Liu, Yuying Zhao, Yaoqin Gong, Chuanzhu Yan
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b8390d700b54a898bb88521874d2d89
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spelling	oai:doaj.org-article:0b8390d700b54a898bb88521874d2d892021-11-18T07:54:52ZUnfolded protein response and activated degradative pathways regulation in GNE myopathy.1932-620310.1371/journal.pone.0058116https://doaj.org/article/0b8390d700b54a898bb88521874d2d892013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23472144/?tool=EBIhttps://doaj.org/toc/1932-6203Although intracellular beta amyloid (Aβ) accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP) deposition including unfolded protein response (UPR), ubiquitin proteasome system (UPS) activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau) and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), calreticulin and calnexin and valosin containing protein (VCP) were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS) and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD) in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.Honghao LiQi ChenFuchen LiuXuemei ZhangWei LiShuping LiuYuying ZhaoYaoqin GongChuanzhu YanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58116 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Honghao Li Qi Chen Fuchen Liu Xuemei Zhang Wei Li Shuping Liu Yuying Zhao Yaoqin Gong Chuanzhu Yan Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
description	Although intracellular beta amyloid (Aβ) accumulation is known as an early upstream event in the degenerative course of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy, the process by which Aβdeposits initiate various degradative pathways, and their relationship have not been fully clarified. We studied the possible secondary responses after amyloid beta precursor protein (AβPP) deposition including unfolded protein response (UPR), ubiquitin proteasome system (UPS) activation and its correlation with autophagy system. Eight GNE myopathy patients and five individuals with normal muscle morphology were included in this study. We performed immunofluorescence and immunoblotting to investigate the expression of AβPP, phosphorylated tau (p-tau) and endoplasmic reticulum molecular chaperones. Proteasome activities were measured by cleavage of fluorogenic substrates. The expression of proteasome subunits and linkers between proteasomal and autophagy systems were also evaluated by immunoblotting and relative quantitative real-time RT-PCR. Four molecular chaperones, glucose-regulated protein 94 (GRP94), glucose-regulated protein 78 (GRP78), calreticulin and calnexin and valosin containing protein (VCP) were highly expressed in GNE myopathy. 20S proteasome subunits, three main proteasome proteolytic activities, and the factors linking UPS and autophagy system were also increased. Our study suggests that AβPP deposition results in endoplasmic reticulum stress (ERS) and highly expressed VCP deliver unfolded proteins from endoplasmic reticulum to proteosomal system which is activated in endoplasmic reticulum associated degradation (ERAD) in GNE myopathy. Excessive ubiquitinated unfolded proteins are exported by proteins that connect UPS and autophagy to autophagy system, which is activated as an alternative pathway for degradation.
format	article
author	Honghao Li Qi Chen Fuchen Liu Xuemei Zhang Wei Li Shuping Liu Yuying Zhao Yaoqin Gong Chuanzhu Yan
author_facet	Honghao Li Qi Chen Fuchen Liu Xuemei Zhang Wei Li Shuping Liu Yuying Zhao Yaoqin Gong Chuanzhu Yan
author_sort	Honghao Li
title	Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
title_short	Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
title_full	Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
title_fullStr	Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
title_full_unstemmed	Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
title_sort	unfolded protein response and activated degradative pathways regulation in gne myopathy.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/0b8390d700b54a898bb88521874d2d89
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_version_	1718422770961874944

Unfolded protein response and activated degradative pathways regulation in GNE myopathy.

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