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Hum Mol Genet. 2015 Apr 1;24(7):1883-97. doi: 10.1093/hmg/ddu605. Epub 2014 Dec 2.

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

Author information

1
MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
2
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
3
Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
4
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
5
Department of Cellular Pathology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
6
UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
7
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK, a.acevedo@har.mrc.ac.uk e.fisher@prion.ucl.ac.uk l.greensmith@ucl.ac.uk.
8
MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK, a.acevedo@har.mrc.ac.uk e.fisher@prion.ucl.ac.uk l.greensmith@ucl.ac.uk.

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 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.

PMID:
25468678
PMCID:
PMC4355022
DOI:
10.1093/hmg/ddu605
[Indexed for MEDLINE]
Free PMC Article

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