Human Molecular Genetics Advance Access originally published online on January 7, 2009
Human Molecular Genetics 2009 18(7):1190-1199; doi:10.1093/hmg/ddp013
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Suppression of GFAP toxicity by 
B-crystallin in mouse models of Alexander disease
1 Waisman Center 2 Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53705, USA 3 Department of Biomolecular Chemistry 271, Nijmegen Center for Molecular Life Sciences, Radboud University, PO Box 9101, NL-6500 HB Nijmegen, The Netherlands 4 National Eye Institute, National Institutes of Health, DHHS, Bethesda, MD 20892, USA
* To whom correspondence should be addressed at: Waisman Center 715, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705, USA. Tel: +1 6082639192; Fax: +1 6082634364; Email: hagemann{at}waisman.wisc.edu
Received December 10, 2008; Revised December 30, 2008; Accepted January 5, 2009
Alexander disease (AxD) is a primary disorder of astrocytes caused by dominant mutations in the gene for glial fibrillary acidic protein (GFAP). These mutations lead to protein aggregation and formation of Rosenthal fibers, complex astrocytic inclusions that contain GFAP, vimentin, plectin, ubiquitin, Hsp27 and 
B-crystallin. The small heat shock protein B-crystallin (Cryab) regulates GFAP assembly, and elevation of Cryab is a consistent feature of AxD; however, its role in Rosenthal fibers and AxD pathology is not known. Here, we show in AxD mouse models that loss of Cryab results in increased mortality, whereas elevation of Cryab rescues animals from terminal seizures. When mice with Rosenthal fibers induced by over-expression of GFAP are crossed into a Cryab-null background, over half die at 1 month of age. Restoration of Cryab expression through the GFAP promoter reverses this outcome, showing the effect is astrocyte-specific. Conversely, in mice engineered to express both AxD-associated mutations and elevated GFAP, which despite natural induction of Cryab also die at 1 month, transgenic over-expression of Cryab results in a markedly reduced CNS stress response, restores expression of the glutamate transporter Glt1 (EAAT2) and protects these animals from death. In its most common form, AxD is a devastating neurodegenerative disease, with early onset, characterized by seizures, spasticity and developmental delays, ultimately leading to death. Cryab plays a critical role in tempering AxD pathology and should be investigated as a therapeutic target for this and other diseases with astropathology.