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UBC Theses and Dissertations

Identification of novel striatal-enriched transcripts and their analysis in Huntingdon's disease Mazarei, Gelareh


Selective neuronal degeneration of caudate and putamen, collectively known as the striatum, is a disease hallmark in Huntington’s disease (HD). In the striatum of HD patients, the largest neuronal sub-population (comprising 90% of the total population), the GABAergic medium spiny projection neurons, are predominantly lost. The exact mechanism(s) behind this specific neurodegeneration is still unknown. Gene expression changes are considered as important pathogenic events during the course of HD. These changes can be due to a variety of different upstream effects including direct transcriptional dysregulation by mutant huntingtin as well as transcriptional changes as secondary effects of neuronal loss. Many expression studies on diseased human post-mortem brain, as well as different mouse models exhibiting striatal degeneration, have demonstrated changes in the expression of many genes. Genome-wide microarray approach is the common technology used in these studies while striatal-enriched systems have also been studied to identify genes implicated in the pathology of HD. While the former approach can often detect thousands of expression changes, the latter has shown how particular genes important to the functions and physiology of the striatum could be involved in specific vulnerability of this region to neurodegeneration. In this study I have used the Serial Analysis of Gene Expression (SAGE) database (www.mouseatlas.org) and compared the mouse striatum to 18 other brain regions to select for striatal-enriched genes. Within these genes, I have identified: 1) known striatal-enriched genes; 2) genes that have not been previously described as striatal-enriched; and 3) potential novel striatal genes in the genome. The expression of these genes was subsequently tested in the YAC 128 mouse model of HD and candidates with altered levels of expression were examined in the human post-mortem caudate samples. Under this investigation, I could identify interesting transcripts with altered levels of expression in the YAC128 mice. Some of these transcripts showed consistent mRNA expression changes in the human post-mortem tissue. Continuation of this project will include further computational and biochemical analysis of candidate striatal-enriched markers and their implications in HD and will be pursued by me as a PhD project. In summary, this Masters of Science project has resulted in the identification of striatal enriched genes that manifest expression changes in the brain of YAC 128 mouse model of RD and human post-mortem RD brain. This can eventually lead to our better understanding of the pre-existing physiological pathways involved in HD pathogenicity of the disease or alternatively, add to our knowledge about novel mechanistic pathways contributing to selective neurodegeneration in this disease.

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