Progressive neuronopathy in transgenic mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis

Cell. 1993 Apr 9;73(1):35-46. doi: 10.1016/0092-8674(93)90158-m.


We generated four transgenic mice with a 34 kb genomic fragment including the complete human neurofilament heavy (NF-H) gene. This human NF-H fragment contained all regulatory elements for tissue-specific expression, and in two transgenic lines, human NF-H proteins were produced at levels up to 2-fold the levels of endogenous mouse NF-H protein. By 3-4 months of age, these NF-H transgenics progressively develop neurological defects and abnormal neurofilamentous swellings that are highly reminiscent of those found in amyotrophic lateral sclerosis (ALS). We propose that a modest up-regulation of NF-H cross-linkers can result in an impairment of neurofilament transport, causing neuronal swellings with ensuing axonopathy and muscle atrophy, a mechanism of pathogenesis pertinent to the possible etiology of ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Axons / pathology
  • Disease Models, Animal
  • Gene Expression / physiology
  • Humans
  • Mice
  • Mice, Transgenic
  • Muscular Atrophy / metabolism
  • Neurofilament Proteins / biosynthesis
  • Neurofilament Proteins / genetics*
  • Neurons / metabolism
  • Neurons / pathology


  • Neurofilament Proteins
  • neurofilament protein H