title: A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity.
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.
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Joyce
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Mcgoldrick
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Rachele A
authors.initials: RA
authors.lastname: Saccon
authors.affiliation: Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: William
authors.initials: W
authors.lastname: Weber
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fratta
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: West
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Carter
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Vinaya
authors.initials: V
authors.lastname: Phatak
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stewart
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Simon
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Saumya
authors.initials: S
authors.lastname: Kumar
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Ines
authors.initials: I
authors.lastname: Heise
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Virginie
authors.initials: V
authors.lastname: Bros-Facer
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: James
authors.initials: J
authors.lastname: Dick
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Corrochano
authors.affiliation: Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Macdonnell J
authors.initials: MJ
authors.lastname: Stanford
authors.affiliation: Department of Cellular Pathology, Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.affiliation: MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
authors.affiliation: UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Meyer
authors.affiliation: MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK.
authors.forename: David L H
authors.initials: DL
authors.lastname: Bennett
authors.affiliation: Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: P Hande
authors.initials: PH
authors.lastname: Ozdinler
authors.affiliation: 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.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: 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.
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.affiliation: 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.
authors.forename: Abraham
authors.initials: A
authors.lastname: Acevedo-Arozena
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000201:enzymology; D020125:Mutation, Missense; D017354:Point Mutation; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1