Differential screening of mutated SOD1 transgenic mice reveals early up-regulation of a fast axonal transport component in spinal cord motor neurons

Neurobiol Dis. 2000 Aug;7(4):274-85. doi: 10.1006/nbdi.2000.0292.


In the present study we analyze the molecular mechanisms underlying motor neuron degeneration in familial amyotrophic lateral sclerosis (FALS). For this, we used a transgenic mouse model expressing the Cu/Zn superoxide dismutase (SOD1) gene with a Gly(86) to Arg (G86R) mutation equivalent to that found in a subset of human FALS. Using an optimized suppression subtractive hybridization method, a cDNA specifically up-regulated during the asymptomatic phase in the lumbar spinal cord of G86R mice was identified by sequence analysis as the KIF3-associated protein (KAP3), a regulator of fast axonal transport. RT-PCR analysis revealed that KAP3 induction was an early event arising long before axonal degeneration. Immunohistochemical studies further revealed that KAP3 protein predominantly accumulates in large motor neurons of the ventral spinal cord. We further demonstrated that KAP3 up-regulation occurs independent of any change in the other components of the kinesin II complex. However, since the ubiquitous KIF1A motor is up-regulated, our results show an early and complex rearrangement of the fast axonal transport machinery in the course of FALS pathology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Axonal Transport / physiology*
  • Disease Models, Animal
  • Histones / metabolism*
  • Kinesin / metabolism
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Mutation, Missense
  • Nerve Degeneration / metabolism*
  • Protozoan Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Sequence Analysis, DNA
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1
  • Up-Regulation


  • Histones
  • KAP3 protein, Crithidia fasciculata
  • Kif3a protein, mouse
  • Protozoan Proteins
  • RNA, Messenger
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Kinesin