Journal
EXPERIMENTAL CELL RESEARCH
Volume 315, Issue 7, Pages 1260-1272Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2008.12.012
Keywords
Glial fibrillary acidic protein (GFAP); Alexander disease; Rosenthal fiber (RF); Astrocytes
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Funding
- NIH [NS42803, NS060120, HD03352]
- Wayne and Jean Roper Wisconsin Distinguished Graduate Fellowship
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Alexander disease is a fatal leukoencephalopathy caused by dominantly-acting coding mutations in GFAP. Previous work has also implicated elevations in absolute levels of GFAP as central to the pathogenesis of the disease. However, identification of the critical astrocyte functions that are compromised by mis-expression of GFAP has not yet been possible. To provide new tools for investigating the nature of astrocyte dysfunction in Alexander disease, we have established primary astrocyte Cultures from two mouse models of Alexander disease, a transgenic that over-expresses wild type human GFAP, and a knock-in at the endogenous mouse locus that mimics a common Alexander disease mutation. We find that mutant GFAP, as well as excess wild type GFAP, promotes formation of cytoplasmic inclusions, disrupts the cytoskeleton, decreases cell proliferation, increases cell death, reduces proteasomal function, and compromises astrocyte resistance to stress. (C) 2008 Elsevier Inc. All rights reserved.
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