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Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD

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Williams, Jared R., Trias, Emiliano, Beilby, Pamela R., Lopez, Nathan I., Labut, Edwin M., Bradford, C. Samuel, Roberts, Blaine R., McAllum, Erin J. +9 more·2016·Neurobiology of Disease
DOI 10.1016/j.nbd.2016.01.020PMC PMC4785045
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Abstract

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.

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  • CuATSM extends life in a mouse model of familial ALS by up to 25%.

    “CuATSM extends life in such mice by up to 25%.”

    From The Effect of the Human Peptide GHK on Gene Expression Relevant to Nervous System Function and Cognitive Decline (2017) · cites this paper as [41]

    The Introduction reports that CuATSM extended life by 15% and 26% in two ALS mouse models, while the Results report a 16% increase in another group. The claim captures a survival benefit, but “up to 25%” does not accurately describe the paper’s figures; its continuously treated CCS-coexpressing mice survived much longer still. (LLM, conf=0.85)

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Authors
Williams, J. R., Trias, E., Beilby, P. R., Lopez, N. I., Labut, E. M., Bradford, C. S., Roberts, B. R., McAllum, E. J., Crouch, P. J., Rhoads, T. W., Pereira, C., Son, M., Elliott, J. L., Franco, M. C., Estévez, A. G., Barbeito, L., & Beckman, J. S.
Affiliations
  • Oregon State University (US)
  • The University of Melbourne (AU)
  • The University of Texas Southwestern Medical Center (US)
  • Institut Pasteur de Montevideo (UY)
Corresponding author
Beckman, Joseph S.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2016-05
Volume
89
Pages
1-9
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2016.01.020
PMC
PMC4785045
OpenAlex
W2282619066
Cited by
163
References
1
Citations by year
2026: 7 · 2025: 14 · 2024: 20 · 2023: 8 · 2022: 19 · 2021: 12 · 2020: 28 · 2019: 9 · 2018: 13 · 2017: 18 · 2016: 15
FWCI
13.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Journal of International Crisis and Risk Communication Research (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Amyotrophic Lateral Sclerosis Association (16-IIP-320)
  • Department of Defense (AL140108)
  • Australian National Health and Medical Research Association (1061550, CDF2 1084972)
  • National Science Foundation (1337774)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
copper chaperone for superoxide dismutase, SOD1 G93A mice, amyotrophic lateral sclerosis, motor neuron disease, copper deficiency, ventral spinal cord, positron emission tomography, survival extension, familial ALS
MeSH terms
Amyotrophic Lateral Sclerosis, Animals, Copper, Electron Transport Complex IV, Disease Models, Animal, Mice, Transgenic, Spinal Cord, Superoxide Dismutase, Molecular Chaperones, Mice, Kaplan-Meier Estimate

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