| First Author | Hilton JB | Year | 2018 |
| Journal | Exp Neurol | Volume | 307 |
| Pages | 118-128 | PubMed ID | 29906423 |
| Mgi Jnum | J:269422 | Mgi Id | MGI:6271452 |
| Doi | 10.1016/j.expneurol.2018.06.006 | Citation | Hilton JB, et al. (2018) 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. Exp Neurol 307:118-128 |
| abstractText | 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). |
