title: Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1.
abstract: Mutations in Cu/Zn superoxide dismutase (SOD1) are linked to motor neuron death in familial amyotrophic lateral sclerosis (ALS) by an unclear mechanism, although misfolded SOD1 aggregates are commonly associated with disease. Proteomic analysis of the transgenic SOD1(G93A) ALS rat model revealed significant up-regulation of endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI) family members in lumbar spinal cords. Expression of SOD1 mutants (mSOD1) led to an up-regulation of PDI in motor neuron-like NSC-34 cells but not other cell lines. Inhibition of PDI using bacitracin increased aggregate production, even in wild type SOD1 transfectants that do not readily form inclusions, suggesting PDI may protect SOD1 from aggregation. Moreover, PDI co-localized with intracellular aggregates of mSOD1 and bound to both wild type and mSOD1. SOD1 was also found in the microsomal fraction of cells despite being a predominantly cytosolic enzyme, confirming ER-Golgi-dependent secretion. In SOD1(G93A) mice, a significant up-regulation of unfolded protein response entities was also observed during disease, including caspase-12, -9, and -3 cleavage. Our findings therefore implicate unfolded protein response and ER stress-induced apoptosis in the patho-physiology of familial ALS. The possibility that PDI may be a therapeutic target to prevent SOD1 aggregation is also raised by this study.
authors.affiliation: Brain Injury and Repair Group, Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, USA. j.atkin@hfi.unimelb.edu.au
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
authors.forename: Manal A
authors.initials: MA
authors.lastname: Farg
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Doris
authors.initials: D
authors.lastname: Tomas
authors.forename: Judith A
authors.initials: JA
authors.lastname: Lysaght
authors.forename: Janelle
authors.initials: J
authors.lastname: Nunan
authors.forename: Alan
authors.initials: A
authors.lastname: Rembach
authors.forename: Phillip
authors.initials: P
authors.lastname: Nagley
authors.forename: Philip M
authors.initials: PM
authors.lastname: Beart
authors.forename: Surindar S
authors.initials: SS
authors.lastname: Cheema
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Horne
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology; D016716:PC12 Cells; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D015854:Up-Regulation / Q000235:genetics
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020169:Caspases; D019704:Protein Disulfide-Isomerases