Beneficial effects of Nrf2 overexpression in a mouse model of Alexander disease.

[alexander disease]

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 Nrf 2 . We sought to test whether further elevation of Nrf 2 would be beneficial in a mouse model of Alexander disease . Forcing overexpression of Nrf 2 in astrocytes of R 236 H 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 . Nrf 2 overexpression also restored body weights of R 236 H mice to near wild-type levels . Nrf 2 regulates several genes involved in homeostasis of the antioxidant molecule glutathione , and the neuroprotective effects of Nrf 2 in other neurological disorders may reflect restoration of glutathione to normal levels . However , glutathione levels in R 236 H mice were not decreased . Nrf 2 overexpression did not change glutathione levels or ratio of reduced to oxidized glutathione (indicative of oxidative stress ) in olfactory bulb , where Nrf 2 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 R 236 H mice . These data suggest that the beneficial effects of Nrf 2 are not mediated through glutathione .

Diseases
Validation

Diseases presenting "brain regions" symptom

22q11.2 deletion syndrome

alexander disease

cadasil

cushing syndrome

fabry disease

krabbe disease

pyruvate dehydrogenase deficiency

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