Human retinoic acid receptor-related orphan receptor alpha1 overexpression protects neurones against oxidative stress-induced apoptosis

J Neurochem. 2006 Mar;96(6):1778-89. doi: 10.1111/j.1471-4159.2006.03708.x.

Abstract

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a transcription factor belonging to the superfamily of nuclear receptors. Disruption of the Rora gene in the mouse results in a defect in the development of Purkinje cells leading to a cerebellar atrophy, which suggests a neuroprotective role for RORalpha. To test this hypothesis, the survival rate of lentiviral-mediated human RORalpha1-overexpressing neurones has been evaluated in response to different stressors disturbing the redox homeostasis, such as beta-amyloid peptide, c(2)-ceramide and H(2)O(2). We show that overexpression of human RORalpha1 provides neuroprotection by increasing the expression of the antioxidant proteins glutathione peroxidase 1 and peroxiredoxin 6, leading to a reduction in the accumulation of stress-induced reactive oxygen species. We further demonstrate that the neuroprotective effect of RORalpha is predominantly mediated by glutathione peroxidase 1 and peroxiredoxin 6. These results suggest a new role for RORalpha in the control of the neuronal oxidative stress and thus represents a new transcription factor of interest in the regulation of reactive oxygen species-induced neurodegenerative processes during ageing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Animals
  • Apoptosis / physiology*
  • Brain / metabolism*
  • Brain / physiopathology
  • Cell Survival / physiology
  • Cells, Cultured
  • Cytoprotection / physiology*
  • Genetic Vectors / genetics
  • Glutathione Peroxidase / metabolism
  • Humans
  • Lentivirus / genetics
  • Mice
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Neurons / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Oxidative Stress / physiology*
  • Peroxidases / metabolism
  • Peroxiredoxin VI
  • Peroxiredoxins
  • Reactive Oxygen Species / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / genetics*
  • Trans-Activators
  • Transfection

Substances

  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RORA protein, human
  • Reactive Oxygen Species
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Rora protein, mouse
  • Trans-Activators
  • Peroxidases
  • glutathione peroxidase GPX1
  • PRDX6 protein, human
  • Peroxiredoxin VI
  • Peroxiredoxins
  • Prdx6 protein, mouse
  • Glutathione Peroxidase