NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

J Clin Invest. 2015 Apr;125(4):1433-45. doi: 10.1172/JCI79735. Epub 2015 Mar 23.

Abstract

Oxidative stress contributes to the loss of neurons in many disease conditions as well as during normal aging; however, small-molecule agents that reduce oxidation have not been successful in preventing neurodegeneration. Moreover, even if an efficacious systemic reduction of reactive oxygen and/or nitrogen species (ROS/NOS) could be achieved, detrimental side effects are likely, as these molecules regulate normal physiological processes. A more effective and targeted approach might be to augment the endogenous antioxidant defense mechanism only in the cells that suffer from oxidation. Here, we created several adeno-associated virus (AAV) vectors to deliver genes that combat oxidation. These vectors encode the transcription factors NRF2 and/or PGC1a, which regulate hundreds of genes that combat oxidation and other forms of stress, or enzymes such as superoxide dismutase 2 (SOD2) and catalase, which directly detoxify ROS. We tested the effectiveness of this approach in 3 models of photoreceptor degeneration and in a nerve crush model. AAV-mediated delivery of NRF2 was more effective than SOD2 and catalase, while expression of PGC1a accelerated photoreceptor death. Since the NRF2-mediated neuroprotective effects extended to photoreceptors and retinal ganglion cells, which are 2 very different types of neurons, these results suggest that this targeted approach may be broadly applicable to many diseases in which cells suffer from oxidative damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Catalase / physiology
  • Catalase / therapeutic use
  • Dependovirus / genetics
  • Genetic Therapy*
  • Genetic Vectors / genetics
  • Genetic Vectors / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / physiology
  • NF-E2-Related Factor 2 / therapeutic use*
  • Nerve Crush
  • Nerve Degeneration
  • Neurons / physiology*
  • Optic Nerve Injuries / physiopathology
  • Optic Nerve Injuries / therapy*
  • Oxidative Stress / physiology*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Retinal Cone Photoreceptor Cells / physiology
  • Retinal Ganglion Cells / physiology
  • Retinitis Pigmentosa / therapy*
  • Superoxide Dismutase / physiology
  • Superoxide Dismutase / therapeutic use
  • Transcription Factors / physiology
  • Transcription Factors / therapeutic use

Substances

  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • Catalase
  • Superoxide Dismutase
  • superoxide dismutase 2