title: Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease.
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.
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA. lapashdaniel@waisman.wisc.edu
authors.forename: Christine M
authors.initials: CM
authors.lastname: LaPash Daniels
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Austin
authors.forename: Danica E
authors.initials: DE
authors.lastname: Rockney
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jacka
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Hagemann
authors.forename: Delinda A
authors.initials: DA
authors.lastname: Johnson
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
mesh_terms: D000367:Age Factors; D038261:Alexander Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000172:deficiency; D005978:Glutathione / Q000378:metabolism; D006639:Histidine / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D006639:Histidine; D001120:Arginine; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione