Demyelination, astrogliosis, and accumulation of ubiquitinated proteins, hallmarks of CNS disease in hsf1-deficient mice
Demyelination, astrogliosis, and accumulation of ubiquitinated proteins, hallmarks of CNS disease in hsf1-deficient mice
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DOI：
10.1523/jneurosci.0006-07.2007
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发表时间：
2007-07-25
影响因子：
5.3
通讯作者：
Mivechi, Nahid F.
中科院分区：
文献类型：
--
作者：
Homma, Sachiko;Jin, Xiongjie;Mivechi, Nahid F.
热休克转录因子（Hsfs）负责热休克反应，这是一个进化上保守的清除受损和聚集蛋白的过程。在秀丽隐杆线虫等含有单一Hsf的生物体中，Hsf水平的降低与年龄相关表型的出现和蛋白质聚集体积累的增加有关。哺乳动物细胞表达三种hsfs (hsf1, hsf2, hsf4)，它们在中枢神经系统稳态中的作用尚不清楚。在这项研究中，我们用突变小鼠检测了单个或多个hsf基因缺失对中枢神经系统的影响。我们的研究结果表明，hsf1（-/-）小鼠表现出进行性髓磷脂损失，并伴有严重的星形胶质细胞增生，并且在缺乏hsf2或hsf4基因的情况下，这种情况会加剧。磁共振成像和行为学研究表明，老年hsf1（-/-）小鼠胼胝体白质束减少，运动活动不足。同时，hsf1（-/-）衰老的中枢神经系统表现出活化的小胶质细胞和凋亡细胞的增加，这些细胞主要对星形胶质细胞特异性标记物GFAP呈阳性。基于在活hsf1（-/-）细胞中表达短寿命泛素化绿色荧光蛋白（GFPu）的研究表明，它们降解泛素化蛋白的能力降低，积累短寿命的GFPu，并积累含有三核苷酸重复序列的GFP的亨廷顿模型（Q103-GFP）的聚集体。同样，hsf1（-/-）脑和星形胶质细胞表现出比野生型更高的泛素化蛋白水平，蛋白质氧化水平增加，对氧化应激的敏感性增加。这些研究表明，哺乳动物hsf基因，特别是hsf1，在生物一生中质量控制机制和中枢神经系统稳态的维持中起着关键作用。
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.