Axonal transport defects are a common phenotype in Drosophila models of ALS

Hum Mol Genet. 2016 Jun 15;25(12):2378-2392. doi: 10.1093/hmg/ddw105. Epub 2016 Apr 7.

Abstract

Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of motor neurons resulting in a catastrophic loss of motor function. Current therapies are severely limited owing to a poor mechanistic understanding of the pathobiology. Mutations in a large number of genes have now been linked to ALS, including SOD1, TARDBP (TDP-43), FUS and C9orf72. Functional analyses of these genes and their pathogenic mutations have provided great insights into the underlying disease mechanisms. Defective axonal transport is hypothesized to be a key factor in the selective vulnerability of motor nerves due to their extraordinary length and evidence that ALS occurs as a distal axonopathy. Axonal transport is seen as an early pathogenic event that precedes cell loss and clinical symptoms and so represents an upstream mechanism for therapeutic targeting. Studies have begun to describe the impact of a few pathogenic mutations on axonal transport but a broad survey across a range of models and cargos is warranted. Here, we assessed the axonal transport of different cargos in multiple Drosophila models of ALS. We found that axonal transport defects are common across all models tested, although they often showed a differential effect between mitochondria and vesicle cargos. Motor deficits were also common across the models and generally worsened with age, though surprisingly there was not a clear correlation between the severity of axonal transport defects and motor ability. These results further support defects in axonal transport as a common factor in models of ALS that may contribute to the pathogenic process.

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Animals, Genetically Modified
  • Axonal Transport / genetics*
  • Axons / metabolism
  • Axons / pathology
  • C9orf72 Protein
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Disease Models, Animal
  • Drosophila / genetics
  • Humans
  • Larva / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutation
  • Proteins / genetics*
  • RNA-Binding Protein FUS / biosynthesis
  • RNA-Binding Protein FUS / genetics*
  • Superoxide Dismutase-1 / genetics

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Proteins
  • RNA-Binding Protein FUS
  • TARDBP protein, human
  • Superoxide Dismutase-1