title: Protein disulfide isomerase in ALS mouse glia links protein misfolding with NADPH oxidase-catalyzed superoxide production.
abstract: Protein disulfide isomerase (PDI) is an oxidoreductase assisting oxidative protein folding in the endoplasmic reticulum of all types of cells, including neurons and glia. In neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), up-regulation of PDI is an important part of unfolded protein response (UPR) that is thought to represent an adaption reaction and thereby protect the neurons. Importantly, studies on animal models of familial ALS with mutant Cu/Zn superoxide dismutase 1 (SOD1) have shown that the mutant SOD1 in astrocytes or microglia strongly regulates the progression of the disease. Here, we found an early up-regulation of PDI in microglia of transgenic (tg) mutant SOD1 mice, indicating that in addition to neurons, UPR takes place in glial cells in ALS. The observation was supported by the finding that also the expression of a UPR marker GADD34 (growth arrest and DNA damage-inducible protein) was induced in the spinal cord glia of tg mutant SOD1 mice. Because mutant SOD1 can cause sustained activation of NADPH oxidase (NOX), we investigated the role of PDI in UPR-induced NOX activation in microglia. In BV-2 microglia, UPR resulted in NOX activation with increased production of superoxide and increased release of tumor necrosis factor-α. The phenomenon was recapitulated in primary rat microglia, murine macrophages and human monocytes. Importantly, pharmacological inhibition of PDI or its down-regulation by short interfering RNAs prevented NOX activation in microglia and subsequent production of superoxide. Thus, results strongly demonstrate that UPR, caused by protein misfolding, may lead to PDI-dependent NOX activation and contribute to neurotoxicity in neurodegenerative diseases including ALS.
authors.affiliation: Department of Neurobiology, AI Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Jaronen
authors.forename: Piia
authors.initials: P
authors.lastname: Vehviläinen
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.forename: Velta
authors.initials: V
authors.lastname: Keksa-Goldsteine
authors.forename: Eveliina
authors.initials: E
authors.lastname: Pollari
authors.forename: Piia
authors.initials: P
authors.lastname: Valonen
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000870:Anterior Horn Cells / Q000201:enzymology; D001253:Astrocytes / Q000201:enzymology; D002460:Cell Line; D004789:Enzyme Activation; D004790:Enzyme Induction; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism; D009118:Muscimol / Q000031:analogs & derivatives / Q000494:pharmacology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D005904:Glial Fibrillary Acidic Protein; C000606290:SOD1 protein, human; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D009118:Muscimol; C020522:thiomuscimol; D011393:Procollagen-Proline Dioxygenase; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse; C526500:P4hb protein, mouse; D019704:Protein Disulfide-Isomerases