A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity

Peter I. Joyce, Philip Mcgoldrick, Rachele A. Saccon, William Weber, Pietro Fratta, Steven J. West, Ning Zhu, Sarah Carter, Vinaya Phatak, Michelle Stewart, Michelle Simon, Saumya Kumar, Ines Heise, Virginie Bros-Facer, James Dick, Silvia Corrochano, Macdonnell J. Stanford, Tu Vinh Luong, Patrick M. Nolan, Timothy MeyerSebastian Brandner, David L.H. Bennett, P. Hande Ozdinler, Linda Greensmith*, Elizabeth M.C. Fisher, Abraham Acevedo-Arozena

*Corresponding author for this work

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 Sod1D83G/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, Sod1D83G/D83G mice also phenocopy the distal axonopathy and hepatocellular carcinoma found in Sod1 null mice (Sod1-/-). These unique mice allow us.

Original languageEnglish (US)
Pages (from-to)1883-1897
Number of pages15
JournalHuman molecular genetics
Volume24
Issue number7
DOIs
StatePublished - Oct 28 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Joyce, P. I., Mcgoldrick, P., Saccon, R. A., Weber, W., Fratta, P., West, S. J., Zhu, N., Carter, S., Phatak, V., Stewart, M., Simon, M., Kumar, S., Heise, I., Bros-Facer, V., Dick, J., Corrochano, S., Stanford, M. J., Luong, T. V., Nolan, P. M., ... Acevedo-Arozena, A. (2014). A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity. Human molecular genetics, 24(7), 1883-1897. https://doi.org/10.1093/hmg/ddu605