Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS.
Hilton, JBW
Kysenius, K
Liddell, JR
Mercer, SW
Paul, B
Beckman, JS
McLean, CA
White, AR
Donnelly, PS
Bush, AI
Hare, DJ
Roberts, BR
Crouch, PJ
- Publisher:
- Springer Nature
- Publication Type:
- Journal Article
- Citation:
- Sci Rep, 2024, 14, (1), pp. 5929
- Issue Date:
- 2024-03-11
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Hilton, JBW | |
dc.contributor.author | Kysenius, K | |
dc.contributor.author | Liddell, JR | |
dc.contributor.author | Mercer, SW | |
dc.contributor.author | Paul, B | |
dc.contributor.author | Beckman, JS | |
dc.contributor.author | McLean, CA | |
dc.contributor.author | White, AR | |
dc.contributor.author | Donnelly, PS | |
dc.contributor.author | Bush, AI | |
dc.contributor.author | Hare, DJ | |
dc.contributor.author | Roberts, BR | |
dc.contributor.author | Crouch, PJ | |
dc.date.accessioned | 2024-08-01T04:26:03Z | |
dc.date.available | 2024-02-28 | |
dc.date.available | 2024-08-01T04:26:03Z | |
dc.date.issued | 2024-03-11 | |
dc.identifier.citation | Sci Rep, 2024, 14, (1), pp. 5929 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | http://hdl.handle.net/10453/179926 | |
dc.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. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | Springer Nature | |
dc.relation.ispartof | Sci Rep | |
dc.relation.isbasedon | 10.1038/s41598-024-55832-w | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Copper | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Superoxide Dismutase | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Mice, Transgenic | |
dc.subject.mesh | Spinal Cord | |
dc.subject.mesh | Ceruloplasmin | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Thiosemicarbazones | |
dc.subject.mesh | Coordination Complexes | |
dc.subject.mesh | Spinal Cord | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Mice, Transgenic | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Copper | |
dc.subject.mesh | Thiosemicarbazones | |
dc.subject.mesh | Ceruloplasmin | |
dc.subject.mesh | Superoxide Dismutase | |
dc.subject.mesh | Coordination Complexes | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Copper | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Superoxide Dismutase | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Mice, Transgenic | |
dc.subject.mesh | Spinal Cord | |
dc.subject.mesh | Ceruloplasmin | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Thiosemicarbazones | |
dc.subject.mesh | Coordination Complexes | |
dc.title | Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS. | |
dc.type | Journal Article | |
utslib.citation.volume | 14 | |
utslib.location.activity | England | |
pubs.organisational-group | University of Technology Sydney | |
pubs.organisational-group | University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences | |
utslib.copyright.status | open_access | * |
dc.rights.license | This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2024-08-01T04:25:58Z | |
pubs.issue | 1 | |
pubs.publication-status | Published online | |
pubs.volume | 14 | |
utslib.citation.issue | 1 |
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.
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