You are not logged in.
Openly accessible

Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis

Roberts,BR, Lim,NK, McAllum,EJ, Donnelly,PS, Hare,DJ, Doble,PA, Turner,BJ, Price,KA, Lim,SC, Paterson,BM, Hickey,JL, Rhoads,TW, Williams,JR, Kanninen,KM, Hung,LW, Liddell,JR, Grubman,A, Monty,JF, Llanos,RM, Kramer,DR, Mercer,JF, Bush,AI, Masters,CL, Duce,JA, Li,QX, Beckman,JS, Barnham,KJ, White,AR and Crouch,PJ 2014, Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis, Journal of neuroscience, vol. 34, no. 23, pp. 8021-8031, doi: 10.1523/JNEUROSCI.4196-13.2014.

Attached Files
Name Description MIMEType Size Downloads
roberts-oraltreatment-2014.pdf Published version application/pdf 2.91MB 43

Title Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis
Author(s) Roberts,BR
Lim,NK
McAllum,EJ
Donnelly,PS
Hare,DJ
Doble,PA
Turner,BJ
Price,KA
Lim,SC
Paterson,BM
Hickey,JL
Rhoads,TW
Williams,JR
Kanninen,KM
Hung,LW
Liddell,JR
Grubman,A
Monty,JF
Llanos,RM
Kramer,DR
Mercer,JF
Bush,AI
Masters,CL
Duce,JA
Li,QX
Beckman,JS
Barnham,KJ
White,AR
Crouch,PJ
Journal name Journal of neuroscience
Volume number 34
Issue number 23
Start page 8021
End page 8031
Total pages 11
Publisher Society for Neuroscience
Place of publication Washington, D.C.
Publication date 2014
ISSN 1529-2401
Keyword(s) Administration, Oral
Age Factors
Amyotrophic Lateral Sclerosis
Animals
Cation Transport Proteins
Chromatography, Gel
Disease Models, Animal
Humans
Locomotion
Mice
Mice, Transgenic
Motor Neurons
Mutation
Organometallic Compounds
Phenotype
Spinal Cord
Superoxide Dismutase
Thiosemicarbazones
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
CU/ZN SUPEROXIDE-DISMUTASE
ALS-LINKED SOD1
WILD-TYPE SOD1
MASS-SPECTROMETRY
SPINAL-CORD
POSTTRANSLATIONAL MODIFICATIONS
HEXANUCLEOTIDE REPEAT
PROLONGS SURVIVAL
BINDING-SITE
FAMILIAL ALS
Summary Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.
Language eng
DOI 10.1523/JNEUROSCI.4196-13.2014
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Society for Neuroscience
Persistent URL http://hdl.handle.net/10536/DRO/DU:30072121

Document type: Journal Article
Collections: School of Life and Environmental Sciences
Open Access Collection
Connect to link resolver
 
Unless expressly stated otherwise, the copyright for items in DRO is owned by the author, with all rights reserved.

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.

Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 29 times in TR Web of Science
Scopus Citation Count Cited 31 times in Scopus
Google Scholar Search Google Scholar
Access Statistics: 180 Abstract Views, 45 File Downloads  -  Detailed Statistics
Created: Fri, 01 May 2015, 15:14:06 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.