Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS
Abstract The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essenti...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-55832-w |
| _version_ | 1827316099582001152 |
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| author | James B. W. Hilton Kai Kysenius Jeffrey R. Liddell Stephen W. Mercer Bence Paul Joseph S. Beckman Catriona A. McLean Anthony R. White Paul S. Donnelly Ashley I. Bush Dominic J. Hare Blaine R. Roberts Peter J. Crouch |
| author_facet | James B. W. Hilton Kai Kysenius Jeffrey R. Liddell Stephen W. Mercer Bence Paul Joseph S. Beckman Catriona A. McLean Anthony R. White Paul S. Donnelly Ashley I. Bush Dominic J. Hare Blaine R. Roberts Peter J. Crouch |
| author_sort | James B. W. Hilton |
| collection | DOAJ |
| description | Abstract The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS. |
| first_indexed | 2024-04-24T23:07:46Z |
| format | Article |
| id | doaj.art-236516f7a4ca40819c0aeb1e8d9cbdfc |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T23:07:46Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-236516f7a4ca40819c0aeb1e8d9cbdfc2024-03-17T12:21:38ZengNature PortfolioScientific Reports2045-23222024-03-011411910.1038/s41598-024-55832-wEvidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALSJames B. W. Hilton0Kai Kysenius1Jeffrey R. Liddell2Stephen W. Mercer3Bence Paul4Joseph S. Beckman5Catriona A. McLean6Anthony R. White7Paul S. Donnelly8Ashley I. Bush9Dominic J. Hare10Blaine R. Roberts11Peter J. Crouch12Department of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneDepartment of Anatomy and Physiology, The University of MelbourneSchool of Geography, Earth and Atmospheric Sciences, The University of MelbourneLinus Pauling Institute and Department of Biochemistry and Biophysics, Oregon State UniversityDepartment of Anatomical Pathology, The Alfred HospitalMental Health Program, Department of Cell and Molecular Biology, Queensland Institute of Biomedical Research BerghoferSchool of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of MelbourneMelbourne Dementia Research Centre, The University of Melbourne and Florey Institute of Neuroscience and Mental HealthAtomic Medicine Initiative, University of Technology SydneyDepartment of Biochemistry, Emory University School of MedicineDepartment of Anatomy and Physiology, The University of MelbourneAbstract The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.https://doi.org/10.1038/s41598-024-55832-w |
| spellingShingle | James B. W. Hilton Kai Kysenius Jeffrey R. Liddell Stephen W. Mercer Bence Paul Joseph S. Beckman Catriona A. McLean Anthony R. White Paul S. Donnelly Ashley I. Bush Dominic J. Hare Blaine R. Roberts Peter J. Crouch Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS Scientific Reports |
| title | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS |
| title_full | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS |
| title_fullStr | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS |
| title_full_unstemmed | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS |
| title_short | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS |
| title_sort | evidence for disrupted copper availability in human spinal cord supports cuii atsm as a treatment option for sporadic cases of als |
| url | https://doi.org/10.1038/s41598-024-55832-w |
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