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The Journal of Neuroscience, October 25, 2006, 26(43):11162-11173; doi:10.1523/JNEUROSCI.3260-06.2006

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Neurobiology of Disease
Alexander Disease-Associated Glial Fibrillary Acidic Protein Mutations in Mice Induce Rosenthal Fiber Formation and a White Matter Stress Response

Tracy L. Hagemann,¹ Jolien X. Connor,¹ and Albee Messing^1,2,3

¹Waisman Center, ²Department of Comparative Biosciences, and ³School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin 53705

Correspondence should be addressed to Dr. Tracy L. Hagemann, Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705. Email: hagemann{at}waisman.wisc.edu

Mutations in the gene for the astrocyte specific intermediate filament, glial fibrillary acidic protein (GFAP), cause the rare leukodystrophy Alexander disease (AxD). To study the pathology of this primary astrocyte defect, we have generated knock-in mice with missense mutations homologous to those found in humans. In this report, we show that mice with GFAP-R76H and -R236H mutations develop Rosenthal fibers, the hallmark protein aggregates observed in astrocytes in AxD, in the hippocampus, corpus callosum, olfactory bulbs, subpial, and periventricular regions. Astrocytes in these areas appear reactive and total GFAP expression is elevated. Although general white matter architecture and myelination appear normal, when crossed with an antioxidant response element reporter line, the mutant mice show a distinct pattern of reporter-gene induction that is especially prominent in the corpus callosum, and histochemical staining reveals accumulation of iron in the same region. The mutant mice have a normal lifespan and show no overt behavioral defects, but are more susceptible to kainate-induced seizures. Although these mice demonstrate increased GFAP expression by themselves, further elevation of GFAP via crosses to GFAP transgenic animals leads to a shift in GFAP solubility, an increased stress response, and ultimately death. The mice do not display the full spectrum of pathology observed in human infantile AxD, but may more closely resemble the adult form of the disease. These studies provide formal proof linking GFAP mutations with Rosenthal fibers and oxidative stress, and correlate gliosis and GFAP protein levels to the severity of the disease.

Key words: Alexander disease; GFAP; astrocyte; Rosenthal fiber; oxidative stress; leukodystrophy

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Received March 2, 2006; revised Sept. 19, 2006; accepted Sept. 22, 2006.

Correspondence should be addressed to Dr. Tracy L. Hagemann, Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705. Email: hagemann{at}waisman.wisc.edu

This article has been cited by other articles:

				G. Tang, Z. Yue, Z. Talloczy, T. Hagemann, W. Cho, A. Messing, D. L. Sulzer, and J. E. Goldman Autophagy induced by Alexander disease-mutant GFAP accumulation is regulated by p38/MAPK and mTOR signaling pathways Hum. Mol. Genet., June 1, 2008; 17(11): 1540 - 1555. [Abstract] [Full Text] [PDF]

				S. Kim and P. A. Coulombe Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm Genes & Dev., July 1, 2007; 21(13): 1581 - 1597. [Abstract] [Full Text] [PDF]

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