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J. Biol. Chem., Vol. 281, Issue 40, 30152-30165, October 6, 2006

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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^*

Julie D. Atkin¹, Manal A. Farg, Bradley J. Turner, Doris Tomas, Judith A. Lysaght, Janelle Nunan, Alan Rembach, Phillip Nagley^¶, Philip M. Beart, Surindar S. Cheema, and Malcolm K. Horne

From the Brain Injury and Repair Group, Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010, Australian Proteome Analysis Facility, New South Wales, and ^¶Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia

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.

Received for publication, April 10, 2006 , and in revised form, July 5, 2006.

^* This work was supported by grants from the National Health and Medical Research Council Program Grant 236805, the ALS Association (U. S. A.), a Motor Neuron Disease Research Institute of Australia Fellowship (to J. D. A.), and National Health and Medical Research Council C. J. Martin Fellowship 359269 (to B. J. T.). This research has been facilitated by access to the Australian Proteome Analysis Facility established under the Australian Government's Major National Research Facilities program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 61-3-8344-1959; Fax: 61-3-9348-1707; E-mail: j.atkin{at}hfi.unimelb.edu.au.

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