Published online before print April 13, 2007

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(American Journal of Pathology. 2007;170:2068-2076.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060898

Vacuolar Leukoencephalopathy with Widespread Astrogliosis in Mice Lacking Transcription Factor Nrf2

Ann F. Hubbs^*, Stanley A. Benkovic, Diane B. Miller, James P. O’Callaghan, Lori Battelli^*, Diane Schwegler-Berry^* and Qiang Ma

From the Experimental Pathology Laboratory,^* Pathology and Physiology Research Branch, and the Chronic Stress and Neurotoxicology Laboratory, Molecular Neurotoxicology Laboratory, and Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia

NFE2-related factor 2 (Nrf2), an oxidant-activated CNC bZip transcription factor, has been implicated in defense against oxidative stress and chemical insults in a range of cell and tissue types, including the central nervous system. Here, we report that deletion of the Nrf2 gene in mice caused vacuolar (spongiform) leukoencephalopathy with widespread astrogliosis. The leukoencephalopathy was present in all Nrf2-null mice more than 10 months of age, was characterized by vacuolar degeneration involving all major brain regions, and was most apparent in the white tracts of the cerebellum and pons. Vacuolar degeneration in white tracts was attributable to myelin unwinding and intramyelinic cysts, and double-label immunofluorescence for 4-hydroxy-2-nonenal and myelin basic protein localized free-radical-induced oxidative damage to the myelin sheath. Moreover, the brains of Nrf2-null mice exhibited widespread astrocyte activation with profusion of glial fibrillary acidic protein-immunoreactive glial processes. The study uncovered a possible physiological role for Nrf2 in maintaining central nervous system myelin. If this role is confirmed, it may suggest new approaches to treating genetically and chemically induced myelin degenerative diseases.