Copper Homeostasis as a Therapeutic Target in Amyotrophic Lateral Sclerosis with SOD1 Mutations

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease affecting both upper and lower motor neurons, and currently, there is no cure or effective treatment. Mutations in a gene encoding a ubiquitous antioxidant enzyme, Cu,Zn-superoxide dismutase (SOD1), have been first identified as a cause of familial forms of ALS. It is widely accepted that mutant SOD1 proteins cause the disease through a gain in toxicity but not through a loss of its physiological function. SOD1 is a major copper-binding protein and regulates copper homeostasis in the cell; therefore, a toxicity of mutant SOD1 could arise from the disruption of copper homeostasis. In this review, we will briefly review recent studies implying roles of copper homeostasis in the pathogenesis of SOD1-ALS and highlight the therapeutic interventions focusing on pharmacological as well as genetic regulations of copper homeostasis to modify the pathological process in SOD1-ALS.

Longitudinal assessment of metal concentrations and copper isotope ratios in the G93A SOD1 mouse model of amyotrophic lateral sclerosis

“…The previous observations of increased Cu concentrations, particularly in mouse models of ALS that involve overexpression of SOD1, may therefore be reflective of the increased amount of SOD1 expressed in these mice. It is further possible that this signal indicates the presence of free, but not bio-available, Cu, rather than a side effect of an increased binding affinity, 82 as previously proposed. A recent review highlighted the increasing evidence for the involvement of partially metalated SOD1 in ALS development, 77 which is supported by work with SOD1 G37R mice whereby Cu was delivered directly to spinal cord mSOD1 via Cu II (atsm).…”

“…the SOD1 G93A mouse model of ALS used in this work) was proposed to lead to increased Cu concentrations in spinal cord tissue, due to a proposed increased affinity of mSOD1 for Cu, making it an effective Cu sink. 82 However, a recent review 77 concluded that partially metalated intermediate SOD1 species may account for the observed SOD1 toxic-gain of function. Taking this into account with an overall increased concentration of the mSOD1 in the SOD1 G93A model, Cu concentrations in ALS affected tissues are therefore expected to increase, compared to healthy controls.…”

Is copper a new target to counteract the progression of chronic diseases?

“…ammonium tetrathiomolybdate, TM) has significantly improved and/or slowed down disease progression in severe phenotypes of ALS transgenic mice recently. 71 We think it should be found that the most efficient way to correct intracellular Cu homeostasis is by choosing drugs able to chelate and stabilize abnormal accumulation of Cu ions. However, to achieve this aim in ASL patients, we should beforehand finely characterize how, when and where Cu accumulates in the spinal cord.…”

ALSUntangled 43: copper

“…SOD1 protein normally binds copper, and this binding helps stabilize the shape (conformation) of the protein. Demetalation, which may occur from specific mutations impairing copper binding or dysfunction in carrier proteins (called chaperones), results in misfolded SOD1 which can form neurotoxic protein aggregates (5,(9)(10)(11)(12). SOD1 normally participates in the distribution of intracellular copper.…”

“…Second, treatment with CuATSM, which specifically releases copper into cells that have a defective electron transport chain, slows mouse disease progression (3,(16)(17)(18)(19). Finally, treatment with chelators that lower spinal cord copper levels can also slow mouse disease progression (9).…”