1. Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease.
- Author
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LaPash Daniels CM, Austin EV, Rockney DE, Jacka EM, Hagemann TL, Johnson DA, Johnson JA, and Messing A
- Subjects
- Age Factors, Alexander Disease genetics, Alexander Disease pathology, Alkaline Phosphatase genetics, Alkaline Phosphatase metabolism, Animals, Arginine genetics, Astrocytes metabolism, Astrocytes pathology, Body Weight genetics, Brain pathology, Chromatography, High Pressure Liquid methods, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Gene Expression Regulation genetics, Glial Fibrillary Acidic Protein genetics, Glutamate-Cysteine Ligase deficiency, Glutathione metabolism, Histidine genetics, Humans, Isoenzymes genetics, Isoenzymes metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation genetics, NF-E2-Related Factor 2 genetics, Nerve Fibers metabolism, Nerve Fibers pathology, RNA, Messenger metabolism, Alexander Disease metabolism, Brain metabolism, Gene Expression Regulation physiology, NF-E2-Related Factor 2 metabolism
- Abstract
Alexander disease is a fatal neurodegenerative disease caused by dominant mutations in glial fibrillary acidic protein (GFAP). The disease is characterized by protein inclusions called Rosenthal fibers within astrocyte cell bodies and processes, and an antioxidant response mediated by the transcription factor Nrf2. We sought to test whether further elevation of Nrf2 would be beneficial in a mouse model of Alexander disease. Forcing overexpression of Nrf2 in astrocytes of R236H GFAP mutant mice decreased GFAP protein in all brain regions examined (olfactory bulb, hippocampus, cerebral cortex, brainstem, cerebellum, and spinal cord) and decreased Rosenthal fibers in olfactory bulb, hippocampus, corpus callosum, and brainstem. Nrf2 overexpression also restored body weights of R236H mice to near wild-type levels. Nrf2 regulates several genes involved in homeostasis of the antioxidant molecule glutathione, and the neuroprotective effects of Nrf2 in other neurological disorders may reflect restoration of glutathione to normal levels. However, glutathione levels in R236H mice were not decreased. Nrf2 overexpression did not change glutathione levels or ratio of reduced to oxidized glutathione (indicative of oxidative stress) in olfactory bulb, where Nrf2 dramatically reduced GFAP. Depletion of glutathione through knock-out of the GCLM (glutamate-cysteine ligase modifier subunit) also did not affect GFAP levels or body weight of R236H mice. These data suggest that the beneficial effects of Nrf2 are not mediated through glutathione.
- Published
- 2012
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