Gelareh Mazarei

“Identification of Novel Striatal-Enriched Transcripts and Their Analysis in Huntington Disease”

BSc, UBC, 2005

Exam location: Centre for Molecular Medicine and Therapeutics (CMMT)

950 West 28th Avenue. Vancouver, B.C.,V5Z 4H4. Meeting room 2027

EXAMINING COMMITTEE

Chair: Dr. Daniel Goldowitz

Supervisory Committee: Dr. Blair Leavitt Research Supervisor (Medical Genetics), Dr. Elizabeth Simpson (Medical Genetics) & Dr. Louis Lefebvre (Medical Genetics)

University Examiners: Dr. Lynn Raymond (Neuroscience, Neurology)

ABSTRACT

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. 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) previously reported striatal-enriched genes; 2) genes that have not been previously described as striatal-enriched; and 3) potential novel striatal transcripts in the genome. The expression of these genes was subsequently tested in the YAC128 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.

In summary, this Master of Science project has resulted in the identification of striatal-enriched genes that manifest expression changes in the brain of YAC128 mouse model of HD and human post-mortem HD brain. This can eventually lead to our better understanding of the physiological pathways involved in selective neurodegeneration in HD.

PUBLICATIONS

Mazarei, G. Neal, S.J., Lu, G., Leavitt, B.R. (Manuscript in preparation). Analysis of novel striatal-enriched transcripts in a mouse model of Huntington disease.

Mazarei, G., Wagner, L.A. (2006) SCA8: A two-way street to pathogenecity. Clin. Genet. 70(5):382-83.

Wagner, L.A., Mazarei, G. (2006) Freeman-Sheldon syndrome and Sheldon-Hall syndrome: contracting new genotypes. Clin. Genet. 70(3):192

PRESENTATIONS

Mazarei, G. Neal, S., Lu, G. and Leavitt, B.R. (2007) Gene expression profiling in the brain of the YAC128 mouse model of Huntington disease. (Society of Neuroscience, San Diego, CA November 2007).

Mazarei, G. Neal, S., Lu, G. and Leavitt, B.R. (2007) Striatal-specific gene expression in a mouse model of Huntington disease. (Child and Family Research Institute’s trainee poster session, Vancouver, BC June 2007)

Mazarei, G., Neal, S., and Leavitt, B.R. (2006) Analysis of striatal-specific gene expression in mouse brain. (UBC Medical Genetics Research Day, Vancouver, BC December 2006).

GRADUATE STUDIES

Field of Study: Huntington disease research, Gene Expression studies inthe brain

Courses:

MEDG 505 Genome Analysis. Drs. P. Hieter, & S. Jones

MEDG 520 Advances in Human Molecular Genetics. Dr. A. Brooks-Wilson

MEDG 530 Advances in Human Genetics. Drs. L. Clarke, M. Harris, & B. Leavitt

MEDG 419 Human Cytogenetics. Drs. W. Robinson, C. Brown, & L. Lefebvre

MEDG 545 Current Topics in Medical Genetics. Drs. L. Conibear, M. Kobor, & B. Leavitt

MEDG 548 Directed Studies Dr. B. Leavitt

AWARDS

Canadian Institutes of Health Research (CIHR), Doctoral Award for Research in Huntington’s Disease. 2009-2012

University Graduate Fellowship, University of British Columbia. 2009-2010

Natural Sciences and Engineering Research Council of Canada (NSERC) PGS-M. 2007-2008

University Graduate Fellowship, University of British Columbia 2007-2008

Gelareh Mazarei Defense Programme - pdf