An investigation of the neurobiology of Rett syndrome via gene expression analysis

This dissertation constitutes an investigation of the neuropathobiology of Rett Syndrome using gene expression analysis methods. Because mutations in the gene encoding a transcriptional regulator, McCP2, lead to Rett Syndrome, gene expression analysis methods, and cDNA microarrays in particular, are especially well-suited to the study of this disorder. Through the analysis of gene expression in postmortem brain tissue we have begun to elucidate the molecular details of the neuropathology of Rett Syndrome. Increased astroglial reactivity in conjunction with impaired neural development, especially presynaptic development, characterize the Rett Syndrome brain. So clear are these molecular characteristics when viewed using gene expression analysis, that Rett Syndrome brain tissue samples can be distinguished from controls using gene expression information alone. In addition, we used the integration of information resident in on-line biological databases into our gene expression data analysis in order to identify possible disease mechanisms in Rett Syndrome. The aberrant over-expression of inappropriate mRNAs resulting from the release of MeCP2-mediated transcriptional silencing may lead to the compensatory down regulation of normally expressed transcripts. Energy metabolism appears to be one of the systems within the brain that is most profoundly disrupted by MECP2 mutation.;This dissertation contains the full description of the approach we have taken (INTRODUCTION page 1), the findings we have made (FINDINGS page 45), and methods used to accomplish this course of research (METHODS page 130).