Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease

Curr Biol. 2003 Apr 15;13(8):669-73. doi: 10.1016/s0960-9822(03)00206-9.


Apoptosis is a hallmark of motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) [1]. In a widely used mouse model of motoneuron disease (progressive motor neuronopathy or pmn) [2-4], transgenic expression of the anti-apoptotic bcl-2 gene [5] or treatment with glial cell-derived neurotrophic factor [6] prevents the apoptosis of the motoneuron soma; however, they were unable to affect the life span of the animals. The goal of the present work was to determine whether the pmn phenotype could be rescued by means of a gene that inhibits axon degeneration. For this reason, the pmn mice were crossed with mice bearing the dominant Wlds ("slow Wallerian degeneration") mutation, which slows axon degeneration and synapse loss [7-9]. We show here that the Wlds gene product attenuates symptoms, extends life span, prevents axon degeneration, rescues motoneuron number and size, and delays retrograde transport deficits in pmn/pmn mice. These results suggest new pathogenic mechanisms and therapeutic avenues for motoneuron diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Axons / pathology*
  • Crosses, Genetic
  • Disease Models, Animal
  • Mice
  • Mice, Transgenic
  • Motor Neuron Disease / pathology*
  • Motor Neuron Disease / physiopathology*
  • Motor Neuron Disease / therapy
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / therapeutic use
  • Neuromuscular Junction / anatomy & histology
  • Staining and Labeling
  • Synapses / pathology*


  • Nerve Tissue Proteins
  • Wld protein, mouse