TitleCopper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SOD.
Publication TypeJournal Article
Year of Publication2016
AuthorsWilliams JR, Trias E, Beilby PR, Lopez NI, Labut EM, C Bradford S, Roberts BR, McAllum EJ, Crouch PJ, Rhoads TW, Pereira C, Son M, Elliott JL, Franco MClara, Estévez AG, Barbeito L, Beckman JS
JournalNeurobiol Dis
Date Published2016 May
KeywordsAmyotrophic Lateral Sclerosis, Animals, Copper, Disease Models, Animal, Electron Transport Complex IV, Kaplan-Meier Estimate, Mice, Mice, Transgenic, Molecular Chaperones, Spinal Cord, Superoxide Dismutase

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.

Alternate JournalNeurobiol. Dis.
PubMed ID26826269
PubMed Central IDPMC4785045
Grant ListR01 NS058628 / NS / NINDS NIH HHS / United States
NS036761 / NS / NINDS NIH HHS / United States
NS058628 / NS / NINDS NIH HHS / United States
AT002034 / AT / NCCIH NIH HHS / United States
R01 NS036761 / NS / NINDS NIH HHS / United States
P01 AT002034 / AT / NCCIH NIH HHS / United States
P30 ES000210 / ES / NIEHS NIH HHS / United States