TY - JOUR
T1 - Demyelination, astrogliosis, and accumulation of ubiquitinated proteins, hallmarks of CNS disease in hsf1-deficient mice
AU - Homma, Sachiko
AU - Jin, Xiongjie
AU - Wang, Guanghu
AU - Tu, Naxin
AU - Min, Jinna
AU - Yanasak, Nathan
AU - Mivechi, Nahid F.
PY - 2007/7/25
Y1 - 2007/7/25
N2 - 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.
AB - 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.
KW - Astrogliosis
KW - Demyelination
KW - Heat shock factors
KW - Knock-out mice
KW - Myelin
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=34547420555&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547420555&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0006-07.2007
DO - 10.1523/JNEUROSCI.0006-07.2007
M3 - Article
C2 - 17652588
AN - SCOPUS:34547420555
SN - 0270-6474
VL - 27
SP - 7974
EP - 7986
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 30
ER -