Human Molecular Genetics Advance Access originally published online on September 9, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 21 2753-2764
DOI: 10.1093/hmg/ddg312
© 2003 Oxford University Press
Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature
1Department of Pathology and 2Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 3Mouse Cancer Genetics Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA
Received June 3, 2003; Revised August 19, 2003; Accepted August 29, 2003
Cu/Zn superoxide dismutase (SOD1), a crucial cellular antioxidant, can in certain settings mediate toxic chemistry through its Cu cofactor. Whether this latter property explains why mutations in SOD1 cause FALS has been debated. Here, we demonstrate motor neuron disease in transgenic mice expressing a SOD1 variant that mutates the four histidine residues that coordinately bind Cu. In-depth analyses of this new mouse model, previously characterized models and FALS human tissues revealed that the accumulation of detergent-insoluble forms of SOD1 is a common feature of the disease. These insoluble species include full-length SOD1 proteins, peptide fragments, stable oligomers and ubiquitinated entities. Moreover, chaperones Hsp25 and 
B-crystallin specifically co-fractionated with insoluble SOD1. In cultured cells, all 11 of the FALS variants tested produced insoluble forms of mutant SOD1. Importantly, expression of recombinant peptide fragments of wild-type SOD1 in cultured cells also produced insoluble species, suggesting that SOD1 possesses elements with an intrinsic propensity to aggregate. Thus, modifications to the protein, such as FALS mutations, fragmentation and possibly covalent modification, may simply act to augment a natural, but potentially toxic, propensity to aggregate.
* To whom correspondence should be addressed at: Department of Pathology, The Johns Hopkins University School of Medicine, 720 Rutland Ave., Room 558, Baltimore, MD 21205, USA. Tel: +1 4105025174; Fax: +1 4109559777; Email: drbor{at}jhmi.edu
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