Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A 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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-05-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116300201 |
| _version_ | 1818646244722999296 |
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| author | Jared R. Williams Emiliano Trias Pamela R. Beilby Nathan I. Lopez Edwin M. Labut C. Samuel Bradford Blaine R. Roberts Erin J. McAllum Peter J. Crouch Timothy W. Rhoads Cliff Pereira Marjatta Son Jeffrey L. Elliott Maria Clara Franco Alvaro G. Estévez Luis Barbeito Joseph S. Beckman |
| author_facet | Jared R. Williams Emiliano Trias Pamela R. Beilby Nathan I. Lopez Edwin M. Labut C. Samuel Bradford Blaine R. Roberts Erin J. McAllum Peter J. Crouch Timothy W. Rhoads Cliff Pereira Marjatta Son Jeffrey L. Elliott Maria Clara Franco Alvaro G. Estévez Luis Barbeito Joseph S. Beckman |
| author_sort | Jared R. Williams |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T00:43:34Z |
| format | Article |
| id | doaj.art-317f96cedfe543dcbf44df3fa341418c |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T00:43:34Z |
| publishDate | 2016-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-317f96cedfe543dcbf44df3fa341418c2022-12-21T22:09:57ZengElsevierNeurobiology of Disease1095-953X2016-05-018919Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SODJared R. Williams0Emiliano Trias1Pamela R. Beilby2Nathan I. Lopez3Edwin M. Labut4C. Samuel Bradford5Blaine R. Roberts6Erin J. McAllum7Peter J. Crouch8Timothy W. Rhoads9Cliff Pereira10Marjatta Son11Jeffrey L. Elliott12Maria Clara Franco13Alvaro G. Estévez14Luis Barbeito15Joseph S. Beckman16Linus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesInstituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay; Institut Pasteur de Montevideo, UruguayLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesFlorey Institute, University of Melbourne, AustraliaFlorey Institute, University of Melbourne, Australia; Department of Pathology, University of Melbourne, AustraliaFlorey Institute, University of Melbourne, Australia; Department of Pathology, University of Melbourne, AustraliaLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United StatesDepartment of Statistics, Oregon State University, United StatesDepartment of Neurology, University of Texas Southwestern, Dallas, Texas, United StatesDepartment of Neurology, University of Texas Southwestern, Dallas, Texas, United StatesBurnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United StatesBurnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United StatesInstitut Pasteur de Montevideo, UruguayLinus Pauling Institute, Department of Biochemistry and Biophysics, Oregon State University, United States; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S0969996116300201SOD1Lou GehrigAmyotrophic lateral sclerosisSuperoxide dismutaseCCS |
| spellingShingle | Jared R. Williams Emiliano Trias Pamela R. Beilby Nathan I. Lopez Edwin M. Labut C. Samuel Bradford Blaine R. Roberts Erin J. McAllum Peter J. Crouch Timothy W. Rhoads Cliff Pereira Marjatta Son Jeffrey L. Elliott Maria Clara Franco Alvaro G. Estévez Luis Barbeito Joseph S. Beckman Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD Neurobiology of Disease SOD1 Lou Gehrig Amyotrophic lateral sclerosis Superoxide dismutase CCS |
| title | Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD |
| title_full | Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD |
| title_fullStr | Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD |
| title_full_unstemmed | Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD |
| title_short | Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD |
| title_sort | copper delivery to the cns by cuatsm effectively treats motor neuron disease in sodg93a mice co expressing the copper chaperone for sod |
| topic | SOD1 Lou Gehrig Amyotrophic lateral sclerosis Superoxide dismutase CCS |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116300201 |
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