The prostate apoptosis response-4 protein participates in motor neuron degeneration in amyotrophic lateral sclerosis

FASEB J. 2000 May;14(7):913-24. doi: 10.1096/fasebj.14.7.913.


Prostate apoptosis response-4 (Par-4), a protein containing a leucine zipper domain within a death domain, is up-regulated in prostate cancer cells and hippocampal neurons induced to undergo apoptosis. Here, we report higher Par-4 levels in lumbar spinal cord samples from patients with amyotrophic lateral sclerosis (ALS) than in lumbar spinal cord samples from neurologically normal patients. We also compared the levels of Par-4 in lumbar spinal cord samples from wild-type and transgenic mice expressing the human Cu/Zn-superoxide dismutase gene with a familial ALS mutation. Relative to control samples, higher Par-4 levels were observed in lumbar spinal cord samples prepared from the transgenic mice at a time when they had hind-limb paralysis. Immunohistochemical analyses of human and mouse lumbar spinal cord sections revealed that Par-4 is localized to motor neurons in the ventral horn region. In culture studies, exposure of primary mouse spinal cord motor neurons or NSC-19 motor neuron cells to oxidative insults resulted in a rapid and large increase in Par-4 levels that preceded apoptosis. Pretreatment of the motor neuron cells with a Par-4 antisense oligonucleotide prevented oxidative stress-induced apoptosis and reversed oxidative stress-induced mitochondrial dysfunction that preceded apoptosis. Collectively, these data suggest a role for Par-4 in models of motor neuron injury relevant to ALS.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Base Sequence
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Cells, Cultured
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Transgenic
  • Motor Neurons / pathology*
  • Oligonucleotides, Antisense / genetics
  • Oxidative Stress
  • Spinal Cord / enzymology
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism


  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • prostate apoptosis response-4 protein
  • Superoxide Dismutase