Strikingly however, the increased level Abmole FG-4592 during the second and third postnatal weeks is significantly higher in mutant mice , suggesting that Bortezomib Eif2b5-mutated brains are forced to employ extra protective means during stressful periods such as times of differentiation, synaptogenesis and massive myelination. The current study reveals the massive effect of a mild point mutation in eIF2B, a key translation initiation factor, on global gene expression in the brain. It provides a plausible explanation of the severity of CACH/VWM disease, despite the ����mere���� 20% reduction in eIF2B enzymatic activity associated with this mutation. Future experiments using system biology approaches will enable the discovery of the molecular circuits involved in this pathology and may provide the basis for rational drug design. For all testing, we used male wild-type and mutant siblings of heterozygote mice that were backcrossed to the C57BL strain. All experimental procedures involving mice were approved by the Tel Aviv University Animal Care Committee according to national guidelines . Pups at different ages as indicated were collected from WT or Eif2b5-mutated mating cages, housed in an animal facility with a 14/10 h light/dark cycle in filtered-top cages supplemented with autoclaved wood chips in laminar flow hoods. Animals were fed autoclavable rodent pellet and sterile water ad libitum throughout the experiments. Mice were decapitated followed by brain removal, separation to cerebrum, brain stem and cerebellum when needed and flash freezing in liquid nitrogen for further use. For all experiments, each sample represents the brain of a single mouse. Differentially expressed gene sets were compared to Gene Ontology biological process annotations and KEGG pathway annotations using the hypergeometric distribution and corrected for multiple testing using the Benjamini and Hochberg FDR method . In order to test if the differentially expressed genes were preferentially expressed in specific brain cell types, we also analyzed two brain cell type-specific gene expression datasets which refer to GEO accessions GSE9566 and GSE13379, respectively]. For each dataset, we first clustered the gene expression patterns using CLICK , manually annotated each cluster based on each expression pattern; and then tested the significance of the overlap between each set of differentially expressed genes in our data and each co-expression cluster using the hypergeometric test. Full gene lists of enrichment results are presented in File S2. The GeneChip Mouse Gene 1.0ST Array , which interrogates 28,853 mouse genes across 770,317 distinct probes, was used for expression profiling. A single chip was used to profile the expression pattern of a single brain. A total of 18 chips were used .