Abstract
To define genes associated with or responsible for the neurodegenerative changes observed in transmissible spongiform encephalopathies, we analyzed gene expression in scrapie-infected mouse brain using "mRNA differential display." The RNA transcripts of eight genes were increased 3-8-fold in the brains of scrapie-infected animals. Five of these genes have not previously been reported to exhibit increased expression in this disease: cathepsin S, the C1q B-chain of complement, apolipoprotein D, and two previously unidentified genes denominated scrapie-responsive gene (ScRG)-1 and ScRG-2, which are preferentially expressed in brain tissue. Increased expression of the three remaining genes, beta2 microglobulin, F4/80, and metallothionein II, has previously been reported to occur in experimental scrapie. Kinetic analysis revealed a concomitant increase in the levels of ScRG-1, cathepsin S, the C1q B-chain of complement, and beta2 microglobulin mRNA as well as glial fibrillary acidic protein and F4/80 transcripts, markers of astrocytosis and microglial activation, respectively. In contrast, the level of ScRG-2, apolipoprotein D, and metallothionein II mRNA was only increased at the terminal stage of the disease. ScRG-1 mRNA was found to be preferentially expressed in glial cells and to code for a short protein of 47 amino acids with a strong hydrophobic N-terminal region.
Highlights
To define genes associated with or responsible for the neurodegenerative changes observed in transmissible spongiform encephalopathies, we analyzed gene expression in scrapie-infected mouse brain using “mRNA differential display.” The RNA transcripts of eight genes were increased 3– 8-fold in the brains of scrapie-infected animals
Reactive astrocytosis has been reported to accompany neuronal degeneration in brains of mice with cerebral overexpression of the interleukin-6 gene [24]. To identify those genes the altered expression of which is associated with or may even be responsible for the neurodegenerative changes observed in transmissible spongiform encephalopathies (TSE), we have systematically analyzed modifications of gene expression in scrapie-infected mouse brain using the mRNA differential display screen described by Liang and Pardee [25] and Liang et al [26]
MRNA Differential Display Screen—To identify mRNA species, the expression of which was increased in scrapie-infected mouse brain, we used the mRNA differential display (DD) strategy [25, 26]
Summary
CLONING OF A NEW SCRAPIE-RESPONSIVE GENE AND THE IDENTIFICATION OF INCREASED LEVELS OF SEVEN OTHER mRNA TRANSCRIPTS*. Reactive astrocytosis has been reported to accompany neuronal degeneration in brains of mice with cerebral overexpression of the interleukin-6 gene [24] To identify those genes the altered expression of which is associated with or may even be responsible for the neurodegenerative changes observed in TSE, we have systematically analyzed modifications of gene expression in scrapie-infected mouse brain using the mRNA differential display screen described by Liang and Pardee [25] and Liang et al [26]. This approach has led to the detection of an increased level of expression of eight cellular genes and the slight decreased expression of one other gene. Pathway suggest that some pathological lesions observed in scrapie may result directly from microglial products
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