Apr 18, 2020

Disrupted copper availability in sporadic ALS: Implications for CuII(atsm) as a treatment option

BioRxiv : the Preprint Server for Biology
J. B. HiltonPeter Crouch

Abstract

Objective: The copper compound CuII(atsm) is in phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) consistently and reproducibly ameliorates neurodegeneration in mutant SOD1 mouse models of ALS where its neuroprotective activity has been ascribed in part to improving availability of copper to essential cuproenzymes. However, SOD1 mutations cause only ~2% of ALS cases with most cases being of unknown aetiology. Therapeutic pertinence of CuII(atsm) to sporadic ALS is therefore unclear. Methods: We assayed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper handling, and the activities of cuproenzymes. Results: The natural distribution of copper is disrupted in sporadic ALS. The ALS-affected tissue has a molecular signature consistent with an unsatiated requirement for copper and cuproenzyme activity is affected. Copper levels are decreased in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Interpretation: Mice expressing mutant SOD1 recapitulate salient features of ALS. The unsatiated requirement for copper that is evident in these m...Continue Reading

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