Neuromuscular effects of G93A-SOD1 expression in zebrafish

Mol Neurodegener. 2012 Aug 31;7:44. doi: 10.1186/1750-1326-7-44.

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis.

Results: We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease.

Conclusions: This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Animals, Genetically Modified
  • Blotting, Western
  • Disease Models, Animal*
  • Humans
  • Motor Activity / genetics
  • Motor Neurons / pathology*
  • Mutation
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Neuromuscular Junction / pathology*
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Zebrafish

Substances

  • SOD1 protein, human
  • Superoxide Dismutase
  • Superoxide Dismutase-1