title: Unfolded protein response and activated degradative pathways regulation in GNE myopathy.
abstract: 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.
authors.affiliation: Department of Neurology, Qilu Hospital of Shandong University, Jinan, China.
authors.forename: Honghao
authors.initials: H
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.forename: Fuchen
authors.initials: F
authors.lastname: Liu
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shuping
authors.initials: S
authors.lastname: Liu
authors.forename: Yuying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.forename: Chuanzhu
authors.initials: C
authors.lastname: Yan
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001706:Biopsy; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D009097:Multienzyme Complexes; D009132:Muscles / Q000473:pathology; D009135:Muscular Diseases / Q000201:enzymology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D056811:Unfolded Protein Response; D000074405:Valosin Containing Protein; D055815:Young Adult
chemical_list: D016564:Amyloid beta-Protein Precursor; D037282:Calreticulin; D018797:Cell Cycle Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; C053387:endoplasmin; D037281:Calnexin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein