Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of Amyotrophic lateral sclerosis

Hum Mol Genet. 2014 Aug 15;23(16):4187-200. doi: 10.1093/hmg/ddu136. Epub 2014 Mar 25.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder in which motor neurons in the spinal cord and motor cortex degenerate. Although the majority of ALS cases are sporadic, mutations in Cu-Zn superoxide dismutase-1 (SOD1) are causative for 10-20% of familial ALS (fALS), and recent findings show that a hexanucleotide repeat expansion in the C9ORF72 gene may account for >30% of fALS cases in Europe. SOD1(G93A) transgenic mice have a phenotype and pathology similar to human ALS. In both ALS patients and SOD1(G93A) mice, the first pathological features of disease manifest at the neuromuscular junction, where significant denervation occurs prior to motor neuron degeneration. Strategies aimed at preventing or delaying denervation may therefore be of benefit in ALS. In this study, we show that Nogo-A levels increase in muscle fibres of SOD1(G93A) mice along with the elevation of markers of neuromuscular dysfunction (CHRNA1/MUSK). Symptomatic treatment of SOD1(G93A) mice from 70 days of age with an anti-Nogo-A antibody (GSK577548) significantly improves hindlimb muscle innervation at 90 days, a late symptomatic stage of disease, resulting in increased muscle force and motor unit survival and a significant increase in motor neuron survival. However, not all aspects of this improvement in anti-Nogo-A antibody-treated SOD1(G93A) mice were maintained at end-stage disease. These results show that treatment with anti-Nogo-A antibody significantly improves neuromuscular function in the SOD1(G93A) mouse model of ALS, at least during the earlier stages of disease and suggest that pharmacological inhibition of Nogo-A may be a disease-modifying approach in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Antibodies / immunology
  • Antibodies / therapeutic use*
  • Disease Models, Animal
  • Disease Progression
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / pathology
  • Muscle Fibers, Slow-Twitch / metabolism
  • Myelin Proteins / immunology*
  • Myelin Proteins / metabolism
  • Nogo Proteins
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1

Substances

  • Antibodies
  • Myelin Proteins
  • Nogo Proteins
  • RTN4 protein, human
  • Rtn4 protein, mouse
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1