Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD

Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the...

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Bibliographic Details
Published in:Neurobiology of disease 2016-05, Vol.89, p.1-9
Main Authors: Williams, Jared R, Trias, Emiliano, Beilby, Pamela R, Lopez, Nathan I, Labut, Edwin M, Bradford, C Samuel, Roberts, Blaine R, McAllum, Erin J, Crouch, Peter J, Rhoads, Timothy W, Pereira, Cliff, Son, Marjatta, Elliott, Jeffrey L, Franco, Maria Clara, Estévez, Alvaro G, Barbeito, Luis, Beckman, Joseph S
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - enzymology
Amyotrophic Lateral Sclerosis - metabolism
Animals
Copper - administration & dosage
Copper - metabolism
Disease Models, Animal
Electron Transport Complex IV - metabolism
Kaplan-Meier Estimate
Mice
Mice, Transgenic
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
Spinal Cord - metabolism
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
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Summary:Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth. Hypothesizing that co-expression of CCS created copper deficiency in spinal cord, we treated these pups with the PET-imaging agent CuATSM, which is known to deliver copper into the CNS within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing Cu, Zn SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within 3 months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression. All ALS patients also express human CCS, raising the hope that familial SOD ALS patients could respond to CuATSM treatment similarly to the CCSxSOD mice.
ISSN:1095-953X
DOI:10.1016/j.nbd.2016.01.020