Evidence for disrupted copper availability in human spinal cord supports CuII(atsm) as a treatment option for sporadic cases of ALS

The copper compound Cu II (atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential co...

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Published in:Scientific reports 2024-03, Vol.14 (1), p.5929-5929, Article 5929
Main Authors: Hilton, James B. W., Kysenius, Kai, Liddell, Jeffrey R., Mercer, Stephen W., Paul, Bence, Beckman, Joseph S., McLean, Catriona A., White, Anthony R., Donnelly, Paul S., Bush, Ashley I., Hare, Dominic J., Roberts, Blaine R., Crouch, Peter J.
Format: Article
Language:English
Subjects:
631/378/1689/1285
692/617/375/365/1917
Amyotrophic lateral sclerosis
Animal models
Ceruloplasmin
Copper
Ferroxidase
Humanities and Social Sciences
multidisciplinary
Mutants
Neurodegenerative diseases
Neuroprotection
Science
Science (multidisciplinary)
Spinal cord
Substantia grisea
Superoxide dismutase
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Summary:The copper compound Cu II (atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (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 Cu II (atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu II (atsm) involving copper availability may also be pertinent to sporadic cases of ALS.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-024-55832-w