M.S. Theses

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Browsing M.S. Theses by Subject "Ataxia."

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    Spinocerebellar Ataxia TYPE 2: Ataxin-2 mechanisms and boold biomarkers
    (Thesis (M.S.) - Bogazici University. Institute for Graduate Studies in Science and Engineering, 2015., 2015.) Şen, Nesli Ece.; Başak, A. Nazlı.; Auburger, Georg.
    Spinocerebellar Ataxia Type 2 is an autosomal dominant movement disorder caused by trinucleotide expansions in the ATXN2 gene (>34 CAG repeats). Intermediate expansions of 26-39 repeats are considered as risk factors for several other neurodegenerative disorders, such as ALS, PD and HSP. Ataxin-2 localizes to the rough-ER, binds to the 3’-UTRs of mRNA molecules together with PABPC1 and modulates ribosomal translation. Under stress conditions, ataxin-2 controls the assembly of stress granules, where it sequesters mRNAs and vital proteins that regulate cellular growth and proliferation. Although ataxin-2 is known to contribute to many cellular processes, its exact function is not entirely understood. In order to elucidate ataxin-2 function and the expansion-related pathogenesis and to identify blood biomarkers of SCA2, the transcriptome profiles of Atxn2 knock-out mice and SCA2 patients from a large pedigree were examined. A cluster of genes, whose products are normally secreted to the extracellular fluids, emerged among the 100 most significantly downregulated genes in the mouse transcriptome data. Significant upregulations of Apo-AI, Hemopexin and SERPINA1 proteins were found in Atxn2-KO mouse liver. Candidate blood RNA biomarkers were inferred from the whole blood transcriptome data of SCA2 patients via either direct unbiased filtration or by focusing on neurodegeneration-associated genes. Independent validations of the candidate genes revealed significant upregulations in ETV7, SERINC2, and ATXN1, along with downregulations in DACT1, MATR3, and PHTF2 in patient blood. Gene Set Enrichment Analysis of the patient transcriptome data presented an enrichment in the Parkinson’s disease pathway, key components of which were further analyzed in the context of ATXN2 knock-down neuroblastoma cells. This thesis exhibits insights into the native function and expansion-induced pathogenesis of ataxin-2 by investigating the downstream effects of ATXN2 deficiency and expansions on global and gene-specific transcription profiles.
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    Spinocerebellar ataxias 8, 12 and 14 in Turkey: molecular bases and genetic analyses
    (Thesis (M.S.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2006., 2006.) Saner, Nazan.; Başak, A. Nazlı.
    Spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous groupof neurodegenerative disorders that are inherited in an autosomal dominant manner. Sincethe clinical symptoms of SCA subtypes significantly overlap, and since there is a high clinical variation even in each SCA subtype, genetic analysis is required for differentialdiagnosis. The prevalence of SCA subtypes differs among populations, thus geneticanalysis is directed based on the population-specific SCA prevalence. This studyinvestigates the distribution of SCA8, SCA12 and SCA14 in Turkish patients, who were previously screened for the six more common SCAs (SCA1, 2, 3, 6, 7 and 17). Molecularanalyses of SCA8 and SCA12 were performed both in SCA patients and in healthycontrols by PCR, followed by GeneScan analysis. SCA8 analysis was performed only forscientific purposes because of its unclear molecular basis. SCA patients and healthy controls were shown to have no expanded SCA8 and SCA12 alleles. Trinucleotide repeatnumbers of SCA8 could be determined in 59 SCA patients and in 60 healthy controls;SCA12 alleles were defined in 92 SCA patients and in 89 healthy controls. The repeatnumbers of SCA patients and healthy controls at SCA 8 and SCA12 loci were found to bein the normal ranges. SCA8 analysis was also performed in PD, AD, HD, FA, SCA1 andSCA2 patients to assist in understanding the complex molecular basis of SCA8. In contrastto the above results, expanded SCA8 alleles were found in one PD, one AD, and one FApatient, including her heterozygous father and her two sisters. The finding of expandedSCA8 alleles in control patient groups questions the disease-causing character of CTG repeat expansion. Finally, exon 4 of the PRKCG, which is responsible for SCA14, wasscreened in SCA patients. DNA sequencing results revealed that the SCA patientsexamined within the framework of this thesis have no mutation or polymorphism in this region.