The accumulation of enzymatically inactive cuproenzymes is a CNS-specific phenomenon of the SOD1^G37R mouse model of ALS and can be restored by overexpressing the human copper transporter hCTR1.

Mutations to the copper-dependent enzyme Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans, and transgenic overexpression of mutant SOD1 represents a robust murine model of the disease. We have previously shown that the copper-containing compound Cu^II(atsm) phenotypically improves mutant SOD1 mice and delivers copper to copper-deficient SOD1 in the CNS to restore its physiological function. Cu^II(atsm) is now in clinical trials for the treatment of ALS. In this study, we demonstrate that cuproenzyme dysfunction extends beyond SOD1 in SOD1^G37R mice to also affect the endogenous copper-dependent ferroxidase ceruloplasmin. We show that SOD1 and ceruloplasmin both accumulate progressively in the SOD1^G37R mouse spinal cord as the animals' ALS-like symptoms progress, yet the biochemical activity of the two cuproenzymes does not increase commensurately, indicating that, as per mutant SOD1, ceruloplasmin accumulates in a copper-deficient form. Consistent with this finding, we show that expression of the human copper transporter 1 (hCTR1) in SOD1^G37R mice increases copper levels in the spinal cord and concurrently restores SOD1 and ceruloplasmin activity. Soluble misfolded SOD1, a proposed driver of pathology in this model, is readily detectable in the SOD1^G37R mouse spinal cord. However, misfolded SOD1^G37R levels do not change in abundance with disease progression and are less abundant than misfolded SOD1 in the spinal cords of age-matched transgenic SOD1^WT mice which do not exhibit an evident ALS-like phenotype. Collectively, these outcomes support a copper malfunction phenomenon in mutant SOD1 mouse models of ALS and a copper-related mechanism of action for the therapeutic agent Cu^II(atsm).

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