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Science 18 September 1998:
Vol. 281. no. 5384, pp. 1851 - 1854
DOI: 10.1126/science.281.5384.1851
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Reports

Aggregation and Motor Neuron Toxicity of an ALS-Linked SOD1 Mutant Independent from Wild-Type SOD1

Lucie I. Bruijn, * Megan K. Houseweart, Shinsuke Kato, Karen L. Anderson, Scott D. Anderson, Eisaku Ohama, Andrew G. Reaume, Rick W. Scott, Don W. Cleveland dagger

Analysis of transgenic mice expressing familial amyotrophic lateral sclerosis (ALS)-linked mutations in the enzyme superoxide dismutase (SOD1) have shown that motor neuron death arises from a mutant-mediated toxic property or properties. In testing the disease mechanism, both elimination and elevation of wild-type SOD1 were found to have no effect on mutant-mediated disease, which demonstrates that the use of SOD mimetics is unlikely to be an effective therapy and raises the question of whether toxicity arises from superoxide-mediated oxidative stress. Aggregates containing SOD1 were common to disease caused by different mutants, implying that coaggregation of an unidentified essential component or components or aberrant catalysis by misfolded mutants underlies a portion of mutant-mediated toxicity.

L. I. Bruijn, M. K. Houseweart, K. L. Anderson, S. D. Anderson, D. W. Cleveland, Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California, La Jolla, CA 92093, USA. S. Kato and E. Ohama, Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago 683, Japan. A. G. Reaume and R. W. Scott, Cephalon, 145 Brandywine Parkway, Westchester, PA 19380, USA.
*   Present address: Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, CT 06492-7660, USA.

dagger    To whom correspondence should be addressed. E-mail: dcleveland{at}ucsd.edu

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Brain 127, 73-88
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Wild-Type Nonneuronal Cells Extend Survival of SOD1 Mutant Motor Neurons in ALS Mice.
A. M. Clement, M. D. Nguyen, E. A. Roberts, M. L. Garcia, S. Boillee, M. Rule, A. P. McMahon, W. Doucette, D. Siwek, R. J. Ferrante, et al. (2003)
Science 302, 113-117
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Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice.
H. Guo, L. Lai, M. E.R. Butchbach, M. P. Stockinger, X. Shan, G. A. Bishop, and C.-l. G. Lin (2003)
Hum. Mol. Genet. 12, 2519-2532
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Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9.
N G Robertson, S A Hamaker, V Patriub, J C Aster, and C C Morton (2003)
J. Med. Genet. 40, 479-486
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Bicarbonate-dependent Peroxidase Activity of Human Cu,Zn-Superoxide Dismutase Induces Covalent Aggregation of Protein: INTERMEDIACY OF TRYPTOPHAN-DERIVED OXIDATION PRODUCTS.
H. Zhang, C. Andrekopoulos, J. Joseph, K. Chandran, H. Karoui, J. P. Crow, and B. Kalyanaraman (2003)
J. Biol. Chem. 278, 24078-24089
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Bioinorganic Chemistry Special Feature: Misfolded CuZnSOD and amyotrophic lateral sclerosis.
J. S. Valentine and P. J. Hart (2003)
PNAS 100, 3617-3622
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Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1.
M. D. Nguyen, M. Boudreau, J. Kriz, S. Couillard-Despres, D. R. Kaplan, and J.-P. Julien (2003)
J. Neurosci. 23, 2131-2140
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Analysis of the Cytosolic Proteome in a Cell Culture Model of Familial Amyotrophic Lateral Sclerosis Reveals Alterations to the Proteasome, Antioxidant Defenses, and Nitric Oxide Synthetic Pathways.
S. Allen, P. R. Heath, J. Kirby, S. B. Wharton, M. R. Cookson, F. M. Menzies, R. E. Banks, and P. J. Shaw (2003)
J. Biol. Chem. 278, 6371-6383
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Phenotypic effects of familial amyotrophic lateral sclerosis mutant Sod alleles in transgenic Drosophila.
R. J. Mockett, S. N. Radyuk, J. J. Benes, W. C. Orr, and R. S. Sohal (2003)
PNAS 100, 301-306
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Global Loss of Na,K-ATPase and Its Nitric Oxide-Mediated Regulation in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.
D. Z. Ellis, J. Rabe, and K. J. Sweadner (2003)
J. Neurosci. 23, 43-51
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Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: Decreased stability of the apo state.
M. J. Lindberg, L. Tibell, and M. Oliveberg (2002)
PNAS 99, 16607-16612
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Mitochondrial Localization of Mutant Superoxide Dismutase 1 Triggers Caspase-dependent Cell Death in a Cellular Model of Familial Amyotrophic Lateral Sclerosis.
H. Takeuchi, Y. Kobayashi, S. Ishigaki, M. Doyu, and G. Sobue (2002)
J. Biol. Chem. 277, 50966-50972
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Oxidation-induced Misfolding and Aggregation of Superoxide Dismutase and Its Implications for Amyotrophic Lateral Sclerosis.
R. Rakhit, P. Cunningham, A. Furtos-Matei, S. Dahan, X.-F. Qi, J. P. Crow, N. R. Cashman, L. H. Kondejewski, and A. Chakrabartty (2002)
J. Biol. Chem. 277, 47551-47556
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Dorfin Ubiquitylates Mutant SOD1 and Prevents Mutant SOD1-mediated Neurotoxicity.
J.-i. Niwa, S. Ishigaki, N. Hishikawa, M. Yamamoto, M. Doyu, S. Murata, K. Tanaka, N. Taniguchi, and G. Sobue (2002)
J. Biol. Chem. 277, 36793-36798
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A Rhodopsin Mutant Linked to Autosomal Dominant Retinitis Pigmentosa Is Prone to Aggregate and Interacts with the Ubiquitin Proteasome System.
M. E. Illing, R. S. Rajan, N. F. Bence, and R. R. Kopito (2002)
J. Biol. Chem. 277, 34150-34160
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Differential gene expression in a cell culture model of SOD1-related familial motor neurone disease.
J. Kirby, F. M. Menzies, M. R. Cookson, K. Bushby, and P. J. Shaw (2002)
Hum. Mol. Genet. 11, 2061-2075
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Neuroprotective Effects of Glial Cell Line-Derived Neurotrophic Factor Mediated by an Adeno-Associated Virus Vector in a Transgenic Animal Model of Amyotrophic Lateral Sclerosis.
L.-J. Wang, Y.-Y. Lu, S.-i. Muramatsu, K. Ikeguchi, K.-i. Fujimoto, T. Okada, H. Mizukami, T. Matsushita, Y. Hanazono, A. Kume, et al. (2002)
J. Neurosci. 22, 6920-6928
   Abstract »    Full Text »    PDF »
Overexpression of HGF Retards Disease Progression and Prolongs Life Span in a Transgenic Mouse Model of ALS.
W. Sun, H. Funakoshi, and T. Nakamura (2002)
J. Neurosci. 22, 6537-6548
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Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis.
F. M. Menzies, M. R. Cookson, R. W. Taylor, D. M. Turnbull, Z. M. A. Chrzanowska-Lightowlers, L. Dong, D. A. Figlewicz, and P. J. Shaw (2002)
Brain 125, 1522-1533
   Abstract »    Full Text »    PDF »
Decreased Metallation and Activity in Subsets of Mutant Superoxide Dismutases Associated with Familial Amyotrophic Lateral Sclerosis.
L. J. Hayward, J. A. Rodriguez, J. W. Kim, A. Tiwari, J. J. Goto, D. E. Cabelli, J. S. Valentine, and R. H. Brown Jr. (2002)
J. Biol. Chem. 277, 15923-15931
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Histidinyl Radical Formation in the Self-peroxidation Reaction of Bovine Copper-Zinc Superoxide Dismutase.
M. R. Gunther, J. A. Peters, and M. K. Sivaneri (2002)
J. Biol. Chem. 277, 9160-9166
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Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).
D. S. Howland, J. Liu, Y. She, B. Goad, N. J. Maragakis, B. Kim, J. Erickson, J. Kulik, L. DeVito, G. Psaltis, et al. (2002)
PNAS
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Mechanisms of neurodegeneration in amyotrophic lateral sclerosis.
S Cluskey and D B Ramsden (2001)
Mol. Pathol. 54, 386-392
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Accelerated S-Nitrosothiol Breakdown by Amyotrophic Lateral Sclerosis Mutant Copper,Zinc-Superoxide Dismutase.
M. A. Johnson, T. L. Macdonald, J. B. Mannick, M. R. Conaway, and B. Gaston (2001)
J. Biol. Chem. 276, 39872-39878
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