Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Investigating the Biological Role of Sialidase Neu4 and Gm3 Synthase Enzymes in a Mouse Model of Tay-Sachs Disease(Izmir Institute of Technology, 2017) Barnar, Talha; Seyrantepe, Volkan; Seyrantepe, Volkan; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of Technologyβ-Hexaminidase A which has role in GM2 degradation in glycosphingolipid pathway is known to be main enzyme for Tay-Sachs disease. Although recessive mutant phenotype of this enzyme causes disease in human, Hexa gene knockout mice show less accumulation of GM2 ganglioside than human. To avoid excess GM2 accumulation, mice uses neuraminidases convert GM2 into GA2. In addition, among neuraminidases, it has been found that Neu4-/-Hexa-/- mice can be good model for Tay-Sachs diseases (Seyrantepe et al., 2010). On the other hand, to prevent GM2 accumulation, blocking GM3 synthase is the finest method because GM3 synthase plays a big part in ganglioside synthesis pathway by producing GM3 that is later converted into GM2 or GD3 ganglioside. In addition, GM3 synthase deficient mice can live longer than 1 year. In this study, Hexa-/-GM3S-/-Neu4-/- mice with single and double variants were produced and brain regions were analyzed with thin-layer chromatography, immunohistochemistry, and real-time PCR methods. This investigation was conducted to clarify real function of GM3S on Tay-Sachs mice model and to search for possible effects of Neu4 in ganglioside pathway. Although GM2 accumulation are present in Hexa-/- and Neu4-/-Hexa-/-mice, analysis of Hexa-/-GM3S-/-Neu4-/-and Hexa-/-GM3S-/- mice revealed that there is no GM2 accumulation without GM3 synthase enzyme. These results are consistent with known ganglioside synthesis pathway. Hexa-/-GM3S-/-Neu4-/- and double deficient Neu4-/-mice variants disclosed change of Neu3 and Neu2 concentration to the wild type mice. In regard of these results, change in other neuraminidase expression is to compensate Neu4 function.Master Thesis Investigating the Biological Role of Sialidase Neu4 and Galnac-T Enzymes in a Mouse Model of Tay-Sachs Disease(Izmir Institute of Technology, 2016) Ateş, Edanur; Seyrantepe, Volkan; Seyrantepe, Volkan; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyTay-Sachs disease is a lysosomal storage disorder that is caused by a mutation in the HexA gene coding for the alpha subunit of lysosomal B-hexosaminidase A. HexA is responsible for the removal of N-acetylglucosamine residue form GM2 ganglioside to convert it into GM3 in the ganglioside degradation pathway. Deficiency of HexA causes neuronal death with progressive neurological degeneration. Neu4 is a sialidese and found in lysosomes. Knock-out mice model of Neu4-/- show different ganglioside pattern than wild type mice and there is increased GD1a and decreased GM1 in brains of mice (Seyrantepe et al. 2008). As previously shown, Neu4 is a modifier gene of HexA. On a previous work (Seyrantepe et al. 2010) Neu4-/-HexA-/- double deficient mouse showed more severe phenotype than HexA-/- deficiency alone. 1,4-N-acetylgalactosaminyltransferase; (Galgt1) is one of the key enzymes in the synthesis of complex gangliosides and it work in reverse direction of HexA. In the deficiency of Galgt1, there is only production of simple gangliosides occurs. Absence of complex gangliosides causes neurological degeneration. Mouse model of Neu4-/-HexA-/-Galgt1-/- was generated as a model of substrate deprivation therapy. That mouse has defects in both ganglioside synthesis and degradation mechanisms, so neither synthesis nor degradation of complex gangliosides will occur. By this mean, effects of Tay-Sachs disease were decreased. On previously shown Neu4 has role in the metabolism of GD1a into GM1. With this study, it was speculated that sialidase Neu4 may play a role in the metabolism of simple gangliosides.