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 Meyer; Sebastian Brandner; David L.H. Bennett; P. Hande Ozdinler; Linda Greensmith; Elizabeth M.C. Fisher; Abraham Acevedo-Arozena

doi:10.1093/hmg/ddu605

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

Neurology

Research output: Contribution to journal › Article › peer-review

48 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 language	English (US)
Pages (from-to)	1883-1897
Number of pages	15
Journal	Human molecular genetics
Volume	24
Issue number	7
DOIs	https://doi.org/10.1093/hmg/ddu605
State	Published - Oct 28 2014

Funding

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.

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

Access to Document

10.1093/hmg/ddu605

Cite this

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

@article{0a2d9271471c491fb96aa6b2daa2eaea,

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 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.",

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

note = "Publisher Copyright: {\textcopyright} The Author 2014.",

year = "2014",

month = oct,

day = "28",

doi = "10.1093/hmg/ddu605",

language = "English (US)",

volume = "24",

pages = "1883--1897",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "7",

}

Joyce, PI, Mcgoldrick, P, Saccon, RA, Weber, W, Fratta, P, West, SJ, Zhu, N, Carter, S, Phatak, V, Stewart, M, Simon, M, Kumar, S, Heise, I, Bros-Facer, V, Dick, J, Corrochano, S, Stanford, MJ, Luong, TV, Nolan, PM, Meyer, T, Brandner, S, Bennett, DLH, Hande Ozdinler, P, Greensmith, L, Fisher, EMC & Acevedo-Arozena, A 2014, 'A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity', Human molecular genetics, vol. 24, no. 7, pp. 1883-1897. https://doi.org/10.1093/hmg/ddu605

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84926482556&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926482556&partnerID=8YFLogxK

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 -

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

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this