TY - JOUR
T1 - Copper-binding-site-null SOD1 causes ALS in transgenic mice
T2 - Aggregates of non-native SOD1 delineate a common feature
AU - Wang, Jiou
AU - Slunt, Hilda
AU - Gonzales, Victoria
AU - Fromholt, David
AU - Coonfield, Michael
AU - Copeland, Neal G.
AU - Jenkins, Nancy A.
AU - Borchelt, David R.
N1 - Funding Information:
We are very grateful to Ms Debbie Swing for her help in transgene injections. We thank Drs Wenxue Li, Michael K. Lee, Guilian Xu and Alena V. Savonenko for their helpful discussion and assistance. This study was supported by the ALS Association, the Muscular Dystrophy Association, and by the Robert Packard Center for ALS Research at Johns Hopkins University.
PY - 2003/11/1
Y1 - 2003/11/1
N2 - 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 αB-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.
AB - 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 αB-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.
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U2 - 10.1093/hmg/ddg312
DO - 10.1093/hmg/ddg312
M3 - Article
C2 - 12966034
AN - SCOPUS:0242524455
SN - 0964-6906
VL - 12
SP - 2753
EP - 2764
JO - Human molecular genetics
JF - Human molecular genetics
IS - 21
ER -