Abstract
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex CuII(atsm) tested for therapeutic efficacy in mice expressing SOD1G93A on a mixed genetic background. Oral administration of CuII(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival. Although the ALS-like phenotype of SOD1G93A mice is instigated by expression of the mutant SOD1, we show the improved phenotype of the CuII(atsm)-treated animals involves an increase in mature mutant SOD1 protein in the disease-affected spinal cord, where concomitant increases in copper and SOD1 activity are also evident. In contrast to these effects in the spinal cord, treating with CuII(atsm) had no effect in liver on either mutant SOD1 protein levels or its activity, indicating a CNS-selective SOD1 response to the drug. These data provide support for CuII(atsm) as a treatment option for ALS as well as insight to the CNS-selective effects of mutant SOD1.
Highlights
Caused by SOD1 mutations; even though the mutant SOD1 is expressed ubiquitously and persistently from birth, the Amyotrophic lateral sclerosis (ALS)-like phenotype only presents relatively late in the animals’ life and is the result of selective degeneration of motor neurons in the CNS3,4
To assess this in the context of the compound’s therapeutic activity, representative central nervous system (CNS) and non-CNS tissues were collected from SOD1G93A mice in which treating with CuII(atsm) translated into a robust therapeutic effect
In the context of the therapeutic agent CuII(atsm), we investigated the bioavailability of Cu as a potential contributing factor
Summary
Caused by SOD1 mutations; even though the mutant SOD1 is expressed ubiquitously and persistently from birth, the ALS-like phenotype only presents relatively late in the animals’ life and is the result of selective degeneration of motor neurons in the CNS3,4. CuII(atsm) – diacetylbis(N(4)-methylthiosemicarbazonato)-CuII – is a CuII complex of a bis(thiosemicarbazone) ligand[5] which has been investigated as a potential therapeutic in animal models of ALS and Parkinson’s disease[6,7,8,9,10] and as a PET imaging agent in the clinic for neurological[11,12,13] and non-neurological conditions[14] It is a low molecular weight compound (MW = 321) that is stable (KA = 1018) and able to cross the blood-brain barrier[15]. Given that the therapeutic activity of CuII(atsm) appears to involve the modulation of Cu bioavailability in vivo[8,10], the present study was undertaken to assess whether CuII(atsm) may increase Cu bioavailability to SOD1 in peripheral tissues or only tissues from the CNS. To assess this in the context of the compound’s therapeutic activity, representative CNS (spinal cord) and non-CNS (liver) tissues were collected from SOD1G93A mice in which treating with CuII(atsm) translated into a robust therapeutic effect
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