A neurotoxic peripherin splice variant in a mouse model of ALS

J Cell Biol. 2003 Mar 17;160(6):939-49. doi: 10.1083/jcb.200205027.


Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Anterior Horn Cells / metabolism*
  • Anterior Horn Cells / pathology
  • Axons / metabolism
  • Axons / pathology
  • Cell Death / genetics*
  • Cells, Cultured
  • Disease Models, Animal*
  • Humans
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism*
  • Lumbar Vertebrae
  • Membrane Glycoproteins*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peripherins
  • Precipitin Tests
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Tumor Cells, Cultured


  • Intermediate Filament Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • PRPH protein, human
  • Peripherins
  • SOD1 G37R protein, mouse
  • Superoxide Dismutase