Journal
NEUROBIOLOGY OF DISEASE
Volume 89, Issue -, Pages 1-9Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2016.01.020
Keywords
SOD1; Lou Gehrig; Amyotrophic lateral sclerosis; Superoxide dismutase; CCS
Categories
Funding
- Amyotrophic Lateral Sclerosis Association [16-IIP-320]
- Department of Defense [AL140108]
- Muscular Dystrophy Association
- Australian National Health and Medical Research Association [1061550]
- Australian government [CDF2 1084972]
- National Science Foundation [1337774]
- [AT002034]
- [NS058628]
- [NS036761]
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1337774] Funding Source: National Science Foundation
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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. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
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