A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity
| Autor: | Tim Meyer, Pietro Fratta, Macdonell J. Stanford, P. Hande Özdinler, Rachele A. Saccon, David L.H. Bennett, Patrick M. Nolan, Michelle Simon, Ines Heise, Peter I. Joyce, Sarah K. Carter, Linda Greensmith, Michelle Stewart, Silvia Corrochano, Steven J. West, Virginie Bros-Facer, Sebastian Brandner, William Weber, Elizabeth M. C. Fisher, Ning Zhu, Vinaya Phatak, James R. T. Dick, Philip McGoldrick, Saumya Kumar, Tu Vinh Luong, Abraham Acevedo-Arozena |
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| Rok vydání: | 2014 |
| Předmět: |
Genetically modified mouse
SOD1 Mutant Mutation Missense Biology medicine.disease_cause Mice 03 medical and health sciences Superoxide Dismutase-1 0302 clinical medicine Mutant protein Genetics medicine Animals Humans Point Mutation Amyotrophic lateral sclerosis Molecular Biology Genetics (clinical) 030304 developmental biology Motor Neurons Phenocopy 0303 health sciences Mutation Superoxide Dismutase Point mutation Amyotrophic Lateral Sclerosis Articles General Medicine medicine.disease Cell biology Mice Inbred C57BL Disease Models Animal 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddu605 |
| Popis: | Transgenic mouse models expressing mutant superoxide dismutase 1 (SOD1) have been critical in furthering our understanding of amyotrophic lateral sclerosis (ALS). However, such models generally overexpress the mutant protein, which may give rise to phenotypes not directly relevant to the disorder. Here, we have analysed a novel mouse model that has a point mutation in the endogenous mouse Sod1 gene; this mutation is identical to a pathological change in human familial ALS (fALS) which results in a D83G change in SOD1 protein. Homozgous Sod1(D83G/D83G) mice develop progressive degeneration of lower (LMN) and upper motor neurons, likely due to the same unknown toxic gain of function as occurs in human fALS cases, but intriguingly LMN cell death appears to stop in early adulthood and the mice do not become paralyzed. The D83 residue coordinates zinc binding, and the D83G mutation results in loss of dismutase activity and SOD1 protein instability. As a result, Sod1(D83G/D83G) mice also phenocopy the distal axonopathy and hepatocellular carcinoma found in Sod1 null mice (Sod1(-/-)). These unique mice allow us to further our understanding of ALS by separating the central motor neuron body degeneration and the peripheral effects from a fALS mutation expressed at endogenous levels. |
| Databáze: | OpenAIRE |
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