Nuclear Erythroid 2-related Factor 2-antioxidative Response Element Signaling Pathway in Motor Cortex and Spinal Cord in Amyotrophic Lateral Sclerosis

J Neuropathol Exp Neurol. 2008 Nov;67(11):1055-62. doi: 10.1097/NEN.0b013e31818b4906.


Oxidative stress and inflammation are important pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). Nuclear erythroid 2-related factor 2 (Nrf2) is a basic region leucine-zipper transcription factor that binds to the antioxidant response element, thereby regulating the expression of many genes that are involved in cellular antioxidant and anti-inflammatory defense. Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH-associated protein 1 (Keap1). We investigated the potential involvement of the Nrf2/antioxidant response element signaling pathway in the selective degeneration of motor neurons in ALS. Nrf2 and Keap1 expression was analyzed in primary motor cortex and spinal cord postmortem tissue samples from ALS patients and controls by in situ hybridization histochemistry, quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In ALS samples, there was a reduction of Nrf2 mRNA and protein expression in neurons, whereas Keap1 mRNA expression was increased in the motor cortex. These results suggest that alterations in this signaling cascade occur in motor neurons in ALS and that they may contribute to chronic motor neuron degeneration.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / pathology*
  • Female
  • Gene Expression Regulation / physiology
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Male
  • Middle Aged
  • Motor Cortex / metabolism*
  • Motor Cortex / pathology
  • Motor Neurons / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction / physiology*
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology


  • Glial Fibrillary Acidic Protein
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • RNA, Messenger