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The Journal of Neuroscience, July 25, 2007, 27(30):7974-7986; doi:10.1523/JNEUROSCI.0006-07.2007
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Neurobiology of Disease
Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease in hsf1-Deficient Mice
Sachiko Homma,1 * Xiongjie Jin,1 * Guanghu Wang,1 * Naxin Tu,1 * Jinna Min,1 Nathan Yanasak,2 andNahid F. Mivechi1,2 1Center for Molecular Chaperone/Radiobiology and Cancer Virology, 2Department of Radiology, Medical College of Georgia, Augusta, Georgia 30912
Correspondence should be addressed to Dr. Nahid F. Mivechi, Medical College of Georgia, 1410 Laney Walker Boulevard, CN-3141A, Augusta, GA 30912. Email: nmivechi{at}mcg.edu.
The heat shock transcription factors (Hsfs) are responsible for the heat shock response, an evolutionarily conserved process for clearance of damaged and aggregated proteins. In organisms such as Caenorhabditis elegans, which contain a single Hsf, reduction in the level of Hsf is associated with the appearance of age-related phenotypes and increased accumulation of protein aggregates. Mammalian cells express three hsfs (hsf1, hsf2, hsf4) and their role in CNS homeostasis remains unclear. In this study, we examined the effects of deletion of single or multiple hsf genes in the CNS using mutant mice. Our results show that hsf1–/– mice display progressive myelin loss that accompanies severe astrogliosis and this is exacerbated in the absence of either the hsf2 or hsf4 gene. Magnetic resonance imaging and behavioral studies indicate reduction in the white matter tracts of the corpus callosum, and deficiencies in motor activity, respectively, in aged hsf1–/– mice. Concomitantly, hsf1–/– aged CNS exhibit increased activated microglia and apoptotic cells that are mainly positive for GFAP, an astrocyte-specific marker. Studies based on the expression of short-lived ubiquitinated green fluorescent protein (GFPu) in living hsf1–/– cells indicate that they exhibit reduced ability to degrade ubiquitinated proteins, accumulate short-lived GFPu, and accumulate aggregates of the Huntington's model of GFP containing trinucleotide repeats (Q103-GFP). Likewise, hsf1–/– brain and astrocytes exhibit higher than wild-type levels of ubiquitinated proteins, increased levels of protein oxidation, and increased sensitivity to oxidative stress. These studies indicate a critical role for mammalian hsf genes, but specifically hsf1, in the quality control mechanisms and maintenance of CNS homeostasis during the organism's lifetime.
Key words: heat shock factors; myelin; astrogliosis; neurodegeneration; demyelination; knock-out mice
Received Aug. 7, 2006; revised May 28, 2007; accepted June 6, 2007.
Correspondence should be addressed to Dr. Nahid F. Mivechi, Medical College of Georgia, 1410 Laney Walker Boulevard, CN-3141A, Augusta, GA 30912. Email: nmivechi{at}mcg.edu.
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