Oligodendrocyte injury in multiple sclerosis: a role for p53

J Neurochem. 2003 May;85(3):635-44. doi: 10.1046/j.1471-4159.2003.01674.x.


Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Caspases / metabolism
  • Cells, Cultured
  • Fas Ligand Protein
  • Gene Transfer Techniques
  • Humans
  • Ligands
  • Membrane Glycoproteins / pharmacology
  • Multiple Sclerosis / etiology
  • Multiple Sclerosis / metabolism*
  • Multiple Sclerosis / pathology
  • Oligodendroglia / drug effects
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Signal Transduction / physiology
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*
  • Up-Regulation
  • fas Receptor / biosynthesis


  • Apoptosis Regulatory Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • Ligands
  • Membrane Glycoproteins
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • Tumor Suppressor Protein p53
  • fas Receptor
  • Caspases