Demyelination, Astrogliosis, and Accumulation of Ubiquitinated Proteins, Hallmarks of CNS Disease inhsf1-Deficient Mice

Abstract

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 Ϫ/Ϫ 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 Ϫ/Ϫ mice. Concomitantly, hsf1 Ϫ/Ϫ 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 hsf1Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease

“…Santos and colleagues noted that their HSF1 KO brains had enlarged ventricles and astrogliosis, particularly in white matter regions (30), while Homma and colleagues also identified diminished myelination in HSF1 KO mice and motor deficiencies (16). Thus, we conducted detailed neuropathological analysis of the HSF1 KO mice from our breeding colony, which is maintained on a mixed 129SV ϫ BALB/c ϫ C57BL/6 background, to determine whether these phenotypes were present.…”

“…It was also reported that HSF1 KO mice have abnormalities in their brains (16,30). Santos and colleagues noted that their HSF1 KO brains had enlarged ventricles and astrogliosis, particularly in white matter regions (30), while Homma and colleagues also identified diminished myelination in HSF1 KO mice and motor deficiencies (16).…”

“…In yeast and Caenorhabditis elegans there is only one HSF gene whereas in mammals there are HSF1, HSF2, and HSF4. Although interplay between HSFs is complex (16), HSF2 and HSF4 have tissue restricted roles, such as in spermatogenesis and lens formation (17)(18)(19)(20). The general picture emerging from gene targeting studies in mice defines HSF1 as the critical global responder to stress (21).…”

Roles of heat shock factor 1 and 2 in response to proteasome inhibition: consequence on p53 stability

“…It would be interesting to determine whether reintroduction of gankyrin in Hsf2 À/À iMEF could restore the level of p53, knowing that it was already shown that gankyrin overexpression accelerates the degradation of p53 in various cell models, including MEF (Higashitsuji et al, 2005). Mivechi's group described a mechanism linking HSF1 deficiency and p53 stabilization (Homma et al, 2007;Jin et al, 2009). Our study confirms a role for HSF1 in the regulation of p53, with a slight stabilization of this protein in pulse-chase experiment compared with WT cells.…”

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

“…On the other hand, HSF1 is reported to be required for extraembryonic development, postnatal growth and fertility of the female in the HSF1-KO mice (47). Homma et al (48) observed hallmarks of central nervous system disease, such as demyelination, astrogliosis and accumulation of ubiquitinated proteins in HSF1-deficient mice. Furthermore, previous studies with HSF1 KO animals have shown that HSF1 is involved in the development and maintenance of several organs, such as the heart (49), trachea (50), nose (50) and placenta (47).…”