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NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Wenjun Xiong, … , Larry I. Benowitz, Constance L. Cepko
Published March 23, 2015
Citation Information: J Clin Invest. 2015;125(4):1433-1445. https://doi.org/10.1172/JCI79735.
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Research Article Genetics Neuroscience Ophthalmology

NRF2 promotes neuronal survival in neurodegeneration and acute nerve damage

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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 Xiong, Alexandra E. MacColl Garfinkel, Yiqing Li, Larry I. Benowitz, Constance L. Cepko

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Figure 1

Expression of endogenous antioxidative enzymes in mouse photoreceptors.

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Expression of endogenous antioxidative enzymes in mouse photoreceptors.
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(A) Schematic illustration of rod and cone death kinetics of the 3 RP mouse models used in this study. (B–E) Immunostaining of endogenous SOD2 (B and C) and GPX1 (D and E) proteins in WT retinal cross-sections. Cone OSs and ISs are highlighted by PNA (green). Both enzymes were enriched in photoreceptor ISs. Arrowheads point to cones, which expressed a higher level of SOD2/GPX1 than did surrounding rods. (F–I) SOD2 (F and G) and GPX1 (H and I) expression in P30 rd1 retina. OSs, ISs, and ONLs had collapsed to a thin layer, and SOD2/GPX1 expression was mostly lost. Scale bars: 5 μm (B–I).

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