Bioinformatics in Neurodegenerative Disease

The brain response to the original viral insult is a crucial aspect of the pathogenesis of AIDS dementia. The study of host gene expression in HIV-1 associated brain disease will facilitate establishing new paradigms and mechanisms for pathogenesis. HIV with only 9 genes is able to destroy its host with more than 30,000 genes. We used gene chip technology (Affymetrix) of brain tissue from AIDS vs. normal brain. As a methods validation model we also used fibroblasts from trisomy patients vs. normal control cells. We found that of 12,600 human genes, 698 are dysregulated in AIDS brain and 257 exhibited dysregulation in Trisomy cells. In the AIDS brain the range of change was from -91.5 to + 54.5 fold. In fibroblasts the range was from -13.2 to 16.9 fold. Gene categorization and preliminary evaluations indicate that in the AIDS vs. normal brain comparison the perturbations in expression occurred including the following genes: 36 kinases, 14 phosphatases, 14 interferon related genes, 11 hormone/neurotransmitters and receptors, 5 glutamate metabolic genes, 2 glutamate receptors, 8 ion channel, TNF and its receptor, IL-1 and IL-4 receptors, superoxide dismutase, 2 Bcl genes, 5 more apoptosis genes, and cyclin. In fibroblasts Trisomy vs. normal cell culture comparisons the perturbations in expression occurred including the following genes that showed different expression from the brain study: 8 kinases, 3 phosphatases, 2 interferon related genes, 6 hormone/neurotransmitters and receptors, 0 glutamate metabolic genes, 0 glutamate receptors, 2 ion channel, 1 calcium binding, 1 ferritin binding, 0 TNF and its receptor, 0 IL-1 and IL-4 receptors, 0 superoxide dismutase, 0 Bcl genes, 5 more apoptosis genes, and 2 cell cycle genes. In addition, the following genes showed differences in their regulation. Trisomy fibroblast changes compared to AIDS brain changes were Proc. Virt. Conf. Genom. and Bioinf.© www.ndsu.edu/virtual-genomics North Dakota State University, USA. Octuber, 15-16, 2001. respectively: 4 vs. 1 metallo-proteinase, 2 vs. 0 proteasome, 1 viral related vs. 1 HIV-1 tat-binding protein, 0 vs. 3 cAMP binding protein response elements, 0 vs. 2 hippocampal adenosine receptor and kinase, 14 vs. 0 glioma and other oncogenes, 14 vs. 0 catabolism/anabolism genes, and 15 vs. 0 ribosomal and translation related genes. Most importantly the following changes also occurred for trisomy vs. AIDS brain comparisons: 0 vs. 2 mental retardation genes, 0 vs. 1 Presenilin-1 gene, 1 vs. 0 Amyloid precursor Protein gene, 1 vs. 0 Down’s syndrome candidate region-1 gene, 2 vs. 2 apo-lipoprotein and receptor, 0 vs. 1 Notch 3 gene, 0 vs. 2 homeobox genes, 1 vs. 0 orofacial digital type 1 syndrome, 1 vs. 0 for both X and Y chromosome genes. This initial assessment indicates a wide range of unanticipated changes in gene expression. Genes involved in cell signaling and gene expression weigh heavily in the brain in AIDS whereas metabolic and oncogene changes occur in the cultures from the Trisomy patient. Distinct changes in a few genes already implicated in the dementia process were found in the Trisomy cultures. However, unanticipated Notch 3 gene and homeobox gene changes occurred in the AIDS brain. This new technology allows identification of genes involved in pathogenesis on a wider scale than hitherto accomplished. Additional studies will be performed for replication of the results.