Oral treatment with Cu(II)(atsm) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis

J Neurosci. 2014 Jun 4;34(23):8021-31. doi: 10.1523/JNEUROSCI.4196-13.2014.

Abstract

Mutations in the metallo-protein Cu/Zn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) in humans and an expression level-dependent phenotype in transgenic rodents. We show that oral treatment with the therapeutic agent diacetyl-bis(4-methylthiosemicarbazonato)copper(II) [Cu(II)(atsm)] increased the concentration of mutant SOD1 (SOD1G37R) in ALS model mice, but paradoxically improved locomotor function and survival of the mice. To determine why the mice with increased levels of mutant SOD1 had an improved phenotype, we analyzed tissues by mass spectrometry. These analyses revealed most SOD1 in the spinal cord tissue of the SOD1G37R mice was Cu deficient. Treating with Cu(II)(atsm) decreased the pool of Cu-deficient SOD1 and increased the pool of fully metallated (holo) SOD1. Tracking isotopically enriched (65)Cu(II)(atsm) confirmed the increase in holo-SOD1 involved transfer of Cu from Cu(II)(atsm) to SOD1, suggesting the improved locomotor function and survival of the Cu(II)(atsm)-treated SOD1G37R mice involved, at least in part, the ability of the compound to improve the Cu content of the mutant SOD1. This was supported by improved survival of SOD1G37R mice that expressed the human gene for the Cu uptake protein CTR1. Improving the metal content of mutant SOD1 in vivo with Cu(II)(atsm) did not decrease levels of misfolded SOD1. These outcomes indicate the metal content of SOD1 may be a greater determinant of the toxicity of the protein in mutant SOD1-associated forms of ALS than the mutations themselves. Improving the metal content of SOD1 therefore represents a valid therapeutic strategy for treating ALS caused by SOD1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Age Factors
  • Amyotrophic Lateral Sclerosis* / drug therapy
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / mortality
  • Amyotrophic Lateral Sclerosis* / pathology
  • Animals
  • Cation Transport Proteins / genetics
  • Chromatography, Gel
  • Coordination Complexes
  • Copper Transporter 1
  • Disease Models, Animal
  • Humans
  • Locomotion / drug effects
  • Locomotion / genetics
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Mutation / genetics*
  • Organometallic Compounds / administration & dosage*
  • Phenotype
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Thiosemicarbazones / administration & dosage*

Substances

  • Cation Transport Proteins
  • Coordination Complexes
  • Copper Transporter 1
  • Organometallic Compounds
  • SLC31A1 protein, human
  • SOD1 protein, human
  • Thiosemicarbazones
  • copper (II) diacetyl-di(N(4)-methylthiosemicarbazone)
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1