title: NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage.
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.
authors: Wenjun
authors: W
authors: Xiong
authors: Alexandra E
authors: AE
authors: MacColl Garfinkel
authors: Yiqing
authors: Y
authors: Li
authors: Larry I
authors: LI
authors: Benowitz
authors: Constance L
authors: CL
authors: Cepko
mesh_terms: D000818:Animals; D017209:Apoptosis; D002374:Catalase / Q000502:physiology / Q000627:therapeutic use; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D009409:Nerve Crush; D009410:Nerve Degeneration; D009474:Neurons / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000503:physiopathology / Q000628:therapy*; D018384:Oxidative Stress / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000628:therapy*; D013482:Superoxide Dismutase / Q000502:physiology / Q000627:therapeutic use; D014157:Transcription Factors / Q000502:physiology / Q000627:therapeutic use; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D051267:NF-E2-Related Factor 2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D013482:Superoxide Dismutase; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2; C495636:Nfe2l2 protein, mouse; C485290:Ppargc1a protein, mouse