Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model

Brain Res. 2004 Nov 19;1027(1-2):73-86. doi: 10.1016/j.brainres.2004.08.054.


The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.

Publication types

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

MeSH terms

  • Age Factors
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Anterior Horn Cells / cytology
  • Anterior Horn Cells / metabolism*
  • Apoptosis / physiology*
  • Biomarkers / metabolism
  • Blotting, Western / methods
  • Caspase 3
  • Caspases / metabolism
  • Cell Count
  • Disease Models, Animal
  • Humans
  • Immunohistochemistry / methods
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mice
  • Mice, Transgenic / physiology
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type I
  • Staining and Labeling / methods
  • Superoxide Dismutase / genetics
  • fas Receptor / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Biomarkers
  • fas Receptor
  • NOS1 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • SOD1 G93A protein
  • Superoxide Dismutase
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases