Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD

Abstract

Over-expression of mutant copper, zinc superoxide dismutase (SOD) in mice induces ALS and has become the most widely used model of neurodegeneration. However, no pharmaceutical agent in twenty years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD (CCS) protein completes the maturation of SOD by inserting copper, but paradoxically human CCS causes mice co-expressing mutant SOD to die within two weeks of birth. Hypothesizing that co-expression of CCS created copper deficiency in spinal cord, we treated these pups with the PET-imaging agent CuATSM, which is known to deliver copper into the CNS within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing Cu,Zn SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within three months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression. All ALS patients also express human CCS, raising the hope that familial SOD ALS patients could respond to CuATSM treatment similarly to the CCSxSOD mice.

The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis

“…The fidelity of this construct was confirmed by sequencing, and retrovirus was produced with the Phoenix amphotrophic packaging cell line (45) and used to transduce MEFs. ATSM was synthesized as described previously (63). Briefly, 5 g of 4-methyl-3-thiosemicarbazide was added to 100 ml of ethanol (100 ml), heated to 60°C, followed by the addition of 2 ml of diacetyl (2,3-butadione).…”

Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis

“…Cu II (atsm), which transports Cu(II) throughout the body and delivers it when it reaches oxidative tissues, has shown a therapeutic effect in several animal models of ALS and PD (Refs 52,63,104,(106)(107)(108). In particular, Cu II (atsm) significantly improves locomotor function and increases mouse survival in SOD1-G93A, SOD1-G37R (Refs 52, 104, 107, 108) and TDP-43 (A315 T) mouse models of ALS (Ref.…”

ALSUntangled 43: copper

“…SOD1 normally participates in the distribution of intracellular copper. Failure of mutant SOD1 to deliver copper to the mitochondria can impair neuronal energy production and increase oxidative stress (3,13). Demetalation of mutant SOD1 can also result in increased copper concentrations in the spinal cord (14).…”

“…First, animals co-expressing human ''copper chaperone for SOD1'' (CCS) have copper deficient mutant SOD1 and markedly accelerated disease progression (15). 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).…”

“…We found several studies evaluating the effect of CuATSM on mutant SOD1 mice with and without CCS coexpression (3,(16)(17)(18)(19). These are summarized in Table 3.…”