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Induction of the Unfolded Protein Response in Familial Amyotrophic Lateral Sclerosis and Association of Protein-disulfide Isomerase with Superoxide Dismutase 1

The Journal of biological chemistry, 2006-10, Vol.281 (40), p.30152-30165 [Peer Reviewed Journal]

2006 © 2006 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M603393200 ;PMID: 16847061

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Title:
Induction of the Unfolded Protein Response in Familial Amyotrophic Lateral Sclerosis and Association of Protein-disulfide Isomerase with Superoxide Dismutase 1
Author: Atkin, Julie D. ; Farg, Manal A. ; Turner, Bradley J. ; Tomas, Doris ; Lysaght, Judith A. ; Nunan, Janelle ; Rembach, Alan ; Nagley, Phillip ; Beart, Philip M. ; Cheema, Surindar S. ; Horne, Malcolm K.
Subjects: Amyotrophic Lateral Sclerosis - enzymology ; Amyotrophic Lateral Sclerosis - genetics ; Animals ; Animals, Genetically Modified ; Caspases - metabolism ; Cell Line, Transformed ; Chlorocebus aethiops ; COS Cells ; Fibroblasts - enzymology ; Humans ; Mice ; Mice, Transgenic ; Motor Neurons - enzymology ; Motor Neurons - pathology ; PC12 Cells ; Protein Disulfide-Isomerases - metabolism ; Protein Folding ; Rats ; Rats, Sprague-Dawley ; Spinal Cord - enzymology ; Spinal Cord - pathology ; Superoxide Dismutase - genetics ; Superoxide Dismutase - metabolism ; Superoxide Dismutase-1 ; Up-Regulation - genetics
Is Part Of: The Journal of biological chemistry, 2006-10, Vol.281 (40), p.30152-30165
Description: 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 SOD1G93A 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 SOD1G93A 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0021-9258
EISSN: 1083-351X
DOI: 10.1074/jbc.M603393200
PMID: 16847061
Source: MEDLINE
PubMed Central
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Induction of the Unfolded Protein Response in Familial Amyotrophic Lateral Sclerosis and Association of Protein-disulfide Isomerase with Superoxide Dismutase 1

2006 © 2006 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M603393200 ;PMID: 16847061

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