TY - JOUR
T1 - A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity
AU - Joyce, Peter I.
AU - Mcgoldrick, Philip
AU - Saccon, Rachele A.
AU - Weber, William
AU - Fratta, Pietro
AU - West, Steven J.
AU - Zhu, Ning
AU - Carter, Sarah
AU - Phatak, Vinaya
AU - Stewart, Michelle
AU - Simon, Michelle
AU - Kumar, Saumya
AU - Heise, Ines
AU - Bros-Facer, Virginie
AU - Dick, James
AU - Corrochano, Silvia
AU - Stanford, Macdonnell J.
AU - Luong, Tu Vinh
AU - Nolan, Patrick M.
AU - Meyer, Timothy
AU - Brandner, Sebastian
AU - Bennett, David L.H.
AU - Hande Ozdinler, P.
AU - Greensmith, Linda
AU - Fisher, Elizabeth M.C.
AU - Acevedo-Arozena, Abraham
N1 - Funding Information:
This work was supported by the Motor Neurone Disease Association (A.A., E.F.), Packard Center for ALS at Johns Hopkins (A.A., E.F., L.G.), Wellcome Trust (DLHB, 095698/Z/11/Z), Medical Research Council (E.F., A.A.) and Les Turner ALS Foundation (P.H.O.). L.G. and E.F. are funded by the European Community’s Seventh Framework Programme (FP7/2007-2013). L.G. is the Graham Watts Senior Research Fellow, funded by The Brain Research Trust. Funding to pay the Open Access publication charges for this article was provided by the Medical Research Council.
Publisher Copyright:
© The Author 2014.
PY - 2014/10/28
Y1 - 2014/10/28
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddu605
DO - 10.1093/hmg/ddu605
M3 - Article
C2 - 25468678
AN - SCOPUS:84926482556
SN - 0964-6906
VL - 24
SP - 1883
EP - 1897
JO - Human molecular genetics
JF - Human molecular genetics
IS - 7
ER -