CuII(atsm) improves the neurological phenotype and survival of SOD1G93A mice and selectively increases enzymatically active SOD1 in the spinal cord

被引：0
作者：
James B. Hilton
Stephen W. Mercer
Nastasia K. H. Lim
Noel G. Faux
Gojko Buncic
Joseph S. Beckman
Blaine R. Roberts
Paul S. Donnelly
Anthony R. White
Peter J. Crouch
机构：
[1] the University of Melbourne,Department of Pathology
[2] Florey Institute of Neuroscience and Mental Health,Department of Biochemistry and Biophysics
[3] the University of Melbourne,undefined
[4] Cooperative Research Centre for Mental Health,undefined
[5] School of Chemistry,undefined
[6] the University of Melbourne,undefined
[7] Linus Pauling Institute,undefined
[8] Oregon State University,undefined
[9] Bio21 Molecular Science and Biotechnology Institute,undefined
[10] the University of Melbourne,undefined
[11] Present address: Shanghai Advanced Research Institute,undefined
[12] Chinese Academy of Sciences,undefined
[13] Pudongxin District,undefined
[14] Shanghai,undefined
[15] China.,undefined
[16] Present address: IBM Research Australia,undefined
[17] Carlton,undefined
[18] Victoria,undefined
[19] Australia.,undefined
[20] Present address: QIMR Berghofer Medical Research Institute,undefined
[21] Herston,undefined
[22] Queensland,undefined
[23] Australia.,undefined
来源：
Scientific Reports | / 7卷
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摘要：
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.
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