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    Cu-II(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord

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    Author
    Hilton, JB; Mercer, SW; Lim, NKH; Faux, NG; Buncic, G; Beckman, JS; Roberts, BR; Donnelly, PS; White, AR; Crouch, PJ
    Date
    2017-02-13
    Source Title
    SCIENTIFIC REPORTS
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Hilton, James; Roberts, Blaine; Donnelly, Paul; White, Anthony; Crouch, Peter; Faux, Noel; Mercer, Stephen; LIM, NASTASIA; BUNCIC, GOJKO
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Clinical Pathology
    Microbiology and Immunology
    Pathology
    Pharmacology and Therapeutics
    School of Chemistry
    Chancellery Research
    Metadata
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    Document Type
    Journal Article
    Citations
    Hilton, J. B., Mercer, S. W., Lim, N. K. H., Faux, N. G., Buncic, G., Beckman, J. S., Roberts, B. R., Donnelly, P. S., White, A. R. & Crouch, P. J. (2017). Cu-II(atsm) improves the neurological phenotype and survival of SOD1(G93A) mice and selectively increases enzymatically active SOD1 in the spinal cord. SCIENTIFIC REPORTS, 7 (1), https://doi.org/10.1038/srep42292.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/234046
    DOI
    10.1038/srep42292
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304223
    Abstract
    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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