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Clinical variability is common in inherited gene defects of the central nervous system in humans and in animal models of human disorders. Here, we used the homozygous spastic (spa) mutant mice, which resemble human hereditary hyperekplexia, to determine the molecular remodeling of the spinal cord through the course of the disease, and develop a model for clinical disparity between littermates. The spa mutation is an insertion of a LINE-1 element in the gene for the beta subunit of the glycine receptor, Glrb. The insertion causes aberrant splicing in the beta subunit of glycine receptor gene with a consequent important reduction of glycine receptors. At young ages, all homozygous spa animals were spastic, showed loss of glycine receptors, increased expression of vesicular glycine/GABA transporter and NMDA receptors, induction of activated caspase3, and preferential loss of glycinergic interneurons consistent with neurotransmitter toxicity model. Those littermates that recovered from symptoms showed strong over-expression of the glycine receptor alpha 1 subunit (Glra1), and increased myelination and synaptic plasticity. Littermates that showed a deteriorating clinical course failed to over-express Glra1, and also showed relative loss of gephyrin (receptor clustering). These molecular changes were associated with a preferential loss of GABAergic interneurons, and extensive motorneuron loss. These data suggest that functional recovery is likely due to expression of homomeric glycine receptors, rescue from excitotoxicity, and subsequent neuronal remodeling. We propose that human patients with hyperekplexia show remodeling similar to that of the recovering spa mice, as human patients also show a lessening of symptoms as a function of age.
Pubmed ID: 16182553 RIS Download
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An experiment in web-database access to large multi-dimensional data sets using a standardized experimental platform to determine if the larger scientific community can be given simple, intuitive, and user-friendly web-based access to large microarray data sets. All data in PEPR is also available via NCBI GEO. The structure and goals of PEPR differ from other mRNA expression profiling databases in a number of important ways. * The experimental platform in PEPR is standardized, and is an Affymetrix - only database. All microarrays available in the PEPR web database should ascribe to quality control and standard operating procedures. A recent publication has described the QC/SOP criteria utilized in PEPR profiles ( The Tumor Analysis Best Practices Working Group 2004 ). * PEPR permits gene-based queries of large Affymetrix array data sets without any specialized software. For example, a number of large time series projects are available within PEPR, containing 40-60 microarrays, yet these can be simply queried via a dynamic web interface with no prior knowledge of microarray data analysis. * Projects in PEPR originate from scientists world-wide, but all data has been generated by the Research Center for Genetic Medicine, Children''''s National Medical Center, Washington DC. Future developments of PEPR will allow remote entry of Affymetrix data ascribing to the same QC/SOP protocols. They have previously described an initial implementation of PEPR, and a dynamic web-queried time series graphical interface ( Chen et al. 2004 ). A publication showing the utility of PEPR for pharmacodynamic data has recently been published ( Almon et al. 2003 ).
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