Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism

J Neuropathol Exp Neurol. 1999 May;58(5):459-71. doi: 10.1097/00005072-199905000-00005.


The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of neuronal death is divisible into 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is internucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectively vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. In contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-xL levels are unchanged in both subcellular compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / pathology*
  • Apoptosis / physiology*
  • Caspase 3
  • Caspases / metabolism
  • Cell Nucleus / pathology
  • DNA Fragmentation
  • Deoxyribonucleases / analysis
  • Female
  • Humans
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Male
  • Membrane Proteins / analysis
  • Middle Aged
  • Mitochondria / enzymology
  • Motor Neurons / chemistry
  • Motor Neurons / cytology*
  • Motor Neurons / enzymology
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / pathology*
  • Poly-ADP-Ribose Binding Proteins
  • Precipitin Tests
  • Proto-Oncogene Proteins / analysis
  • Proto-Oncogene Proteins c-bcl-2*
  • Subcellular Fractions / chemistry
  • Subcellular Fractions / enzymology
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein


  • BAK1 protein, human
  • BAX protein, human
  • Membrane Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • DFFB protein, human
  • Deoxyribonucleases
  • CASP3 protein, human
  • Caspase 3
  • Caspases