TitleEvidence for disrupted copper availability in human spinal cord supports Cu(atsm) as a treatment option for sporadic cases of ALS.
Publication TypeJournal Article
Year of Publication2024
AuthorsHilton 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
JournalSci Rep
Date Published2024 Mar 11
KeywordsAmyotrophic Lateral Sclerosis, Animals, Ceruloplasmin, Coordination Complexes, Copper, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Neurodegenerative Diseases, Spinal Cord, Superoxide Dismutase, Superoxide Dismutase-1, Thiosemicarbazones

The copper compound Cu(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu(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(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for Cu(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

Alternate JournalSci Rep
PubMed ID38467696
PubMed Central ID5304223