Copper homeostasis as a therapeutic goal in amyotrophic lateral sclerosis with a mutation in superoxide dismutase 1 and CuATSM molecule

Authors: P. Hemerková;  M. Vališ
Authors‘ workplace: Neurologická klinika LF UK a FN Hradec Králové
Published in: Cesk Slov Neurol N 2020; 83(1): 21-27
Category: Review Article
doi: 10.14735/amcsnn202021


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons in the cerebral cortex, brain stem, and spinal cord leading to loss of muscle control and death from respiratory failure occurring mostly within 3–5 years of the disease diagnosis. The majority of ALS cases are sporadic (sALS); however, 5–10% are familial cases (fALS). Approximately 20% of fALS cases and 2–7% of sALS cases are associated with a mutation in the SOD1 gene that encodes the copper-zinc superoxide dismutase 1 enzyme (SOD1). The most common free radical arising in the human body is a not very reactive, and thus, not a very harmful superoxide which, however, is capable of spontaneous conversion by dismutation to hydrogen peroxide. SOD1 accelerates this dismutation and the produced hydrogen peroxide is eliminated by successive reactions. The mutations affecting SOD1 lead to copper dyshomeostasis in the spinal cord of animal (mice) models of ALS. Currently, the Cu2+ diacetyl-di, N4-methylthiosemicarbazone molecule is being tested in Australia in a phase I/II clinical trial in patients with ALS. It is assumed that this molecule could work not only in cases of ALS with SOD1 mutation (SOD1-ALS) as a copper or zinc carrier allowing their interaction with SOD1, and thus, it’s the proper function of the enzyme, but also as a compound for peroxynitrite uptake. As a result, its therapeutic use appears not to be limited only to cases of SOD1-ALS or ALS in general, but it might also have an effect as a compound to reduce cell damage by oxidative and nitrosative stress in other neurodegenerative diseases.


amyotrophic lateral sclerosis – copper-zinc superoxide dismutase – Cu2+ diacetyl-di, N4-methylthiosemicarbazone


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