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Issue 9, 2016
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Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS

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Abstract

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, a fatal degenerative disorder in which motor neurons in the central nervous system (CNS) progressively deteriorate. Most cases of ALS are sporadic, but 10% are familial and mutations affecting the copper (Cu)-dependent antioxidant Cu/Zn-superoxide dismutase (SOD1) are the most common familial cause. Cu malfunction is evident in CNS tissue from transgenic mice that over-express mutant SOD1 and modulating Cu bioavailability in the CNS provides positive therapeutic outcomes. In the present study we assessed levels of Cu and Zn, SOD activity, and SOD1 protein levels in CNS and non-CNS tissue from transgenic mutant SOD1 mice (SOD1G37R) and non-transgenic controls. Physiological SOD1 binds one structural Zn and one catalytic Cu per subunit. Due to over-expression of the transgene, SOD activity and SOD1 protein levels are elevated in all tissues examined from the SOD1G37R mice and a commensurate increase in Zn is evident. There is a comparable increase in Cu in non-CNS tissue, but the increase in Cu in the SOD1G37R mouse brain is limited and there is no increase in Cu in the spinal cord. The limited change in CNS Cu is associated with a strong disparity between SOD1 protein and SOD activity in the brain and spinal cord. We hypothesise that the limited capacity for CNS tissue to respond to an increased requirement for bioavailable Cu contributes to CNS vulnerability in ALS.

Graphical abstract: Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS

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Publication details

The article was received on 15 Apr 2016, accepted on 14 Jun 2016 and first published on 22 Jun 2016


Article type: Paper
DOI: 10.1039/C6MT00099A
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Metallomics, 2016,8, 1002-1011
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    Endogenous Cu in the central nervous system fails to satiate the elevated requirement for Cu in a mutant SOD1 mouse model of ALS

    J. B. Hilton, A. R. White and P. J. Crouch, Metallomics, 2016, 8, 1002
    DOI: 10.1039/C6MT00099A

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